DK2968650T3

DK2968650T3 - EYE PHARMACEUTICAL FORMULATIONS FOR THE POSTERIOR EYE SEGMENT

Info

Publication number: DK2968650T3
Application number: DK14724204.4T
Authority: DK
Inventors: David P Bingaman; Paul G Chaney; Martin B Wax
Original assignee: Panoptica Inc
Priority date: 2013-03-14
Filing date: 2014-03-14
Publication date: 2019-03-11
Also published as: US20160354349A1; RU2768489C2; IL240510B; AU2019202857A1; PT2968650T; ZA201907176B; IL276016A; RU2665953C2; TR201901462T4; CN111789814A; AU2017210543B2; AU2014239252B2; HUE042528T2; ES2710152T3; PH12019501902A1; CN105142686A; EP2968650B1; AU2017210543A1; ZA201505447B; EP2968650A1

Description

FIELD OF iNWENTiON

[0001] Embodiments disclosed herein ere generally directed to topical administration of a pharmaceutical compound or a salt thereof to treat ocular diseases or conditions. The embodiments disclosed include ocuiar formulations of a pharmace-uticai compound at salt thereof, where the formulation is a suspension.

BACKGROUND

[0082] Treatment of diseases or disorders of the posterior segment of the eye with topically applied active agents has not been effective because of inefficient delivery of the active agent to the target site. The vast majority of topical drugs penetrate via the comes. However, the cornea is not equally permeable to al! topicatty applied active agents, since the basic st rue to re of the cornea dictates the relative penetration of active agent. Effectively, the greatest barrier to active agent penetration is the cornea! epithelium which is rich in cellular membranes and is therefore more susceptihfe to penetration by active agents which are tipophitic. to contrast, since the cornea) stroma is largely constituted of water, active agents pass more readily through this thickest component of the cornea if they are hydrcphiiic. The endothelium represents a monolayer that, once more, is lipophilic. Active agents which are lipophilic o' amphiphilic, in that they can behave as either charged or non-charged, penetrate the cornea best. Similar to the cornea, the conjunctiva! epithelium and blood vessels within or under the conj unc-ival epithefium may be penetrated by foe same type of bpophifie or bi phasic agents. However, because of the nature oi the lipophilic membranes tn the conjunctive and its inherent vasculature, most active agents typically do not penetrate through the conjunctiva and tnto the eye. Agents with limited penetration tnto the vascular tissues in the conjunctival and subconjunctival regions are drained into ‘he systemic circulation. [0003] !f art aoiive: agent gam s access through the cornea into the anterior chamber, barriers to successful drug delivery to posterior segment tissues such as the retina and choroid- stitt exist These barriers consist of, at least in part, passive barrier's such as aqueous humor flow dynamics: tens and lens zenutes. and a large viireous volume, as well as active barriers, such as cellular transporters or pumps focated in the ciliary epithelium or :n ionic gradients established in the eye [0004] Despite the challenges in defivering drugs topically to the posterior segment of the eye, there ara severe! advantages of this routs of administration over systemic delivery and over intrayiLes! or subconjunctival delivery, tntra-vi-real and subconjunctiva! injections typically reiy on the use of a needle affixed to a syringe to penetrate either the wall of the eye or Ihe conjunctival -issue ίο deliver aqueous pharmacological agents or aqueous suspensions o; agents (e.g . steroids) for acute treatment. However it should also be noted that an increasing number of modalities can deliver sustained payload via vehicle devices such as polymers, organic ceits, or nanoparttcies to deliver the active agent therapeutic agent for a sustained or prolonged period of period ci iime. Topical deliver»/ allows direct application to ihe target organ-the eye. with retative ease of application for the majority of patients. and due to targeted application, ;he need for smalter doses of the active agent associated with onset of action, often resulting in reduced or nonexistent systemic exposure. Disadvantages of topical delivery inctude: contamination of topical drops, the potential requirement tor preservatives, ihe potential toxicity of the drug or ihe preservative to the ocular surface, the limitation of the penetration of most, topical active agents via conjunctiva, cornea. and the anterior chamber, arid the risk, although significantly smaller compared to systemic delivery, of systemic absorption of drugs which may act on other organs - such as the heart and lungs. Weli-recognized complications ofinfravitreat injection include infection, retina! detachment, hemorrhage end scarring. The complications of subconjunctival injection also include infection, scarring, hemorrhage and inadvertent penetration of the globe.

[0005] Because of the limited permeability of many topical drops to the corneal and conjunctive! harriers, one major disadvantage of topical drops, may be the need for high concentration of active agents in the topical formulation in order to achieve meaningful therapeutic drug levels in the eye. Depending on Ute active agent, the concentration in the topical formulation may be highly toxic to the anterior segment of the eye, including the cornea and tens. Therefore, treating diseases or disorders of the posterior segment of the eye would benefit from formutations that allow Sow bioavaiiabitiiy of the active agent a; the anterior segment, while providing availability of an effective concentration of the active at ihe posterior segment, [0006] The Current embodiments provide novel formulations which circumvent the problems encountered in ocular detivery of existing topical therapeutic agents. The current invention accomplishes the combined effects of decreasing corneal and anterior segment drug exposure, while increasing posterior segment bioevailafoiiity By towering corneal exposure and increasing posterior segment bioavailabitity, the formulation of the current invention improves ocular tolerability and increases therapeutic index of the active agent [0007] US“A-2065/074497 discloses hydrogels used to deliver medicaments to the eye for the treatment of posterior -segment diseases.

SUMMARY OF THE INVENTiON

[oao8] The present invention relates to pharmaceutical farmuiations in form iff a suspension. which lower exposure to the active aeerii in the anterior segment of the eye. for example the cornea, while increasing the bioavsliabliity of the agent at the posterior segment of the eye, for example et the central choroid and/or the centre! ratine.

[0009] Two distinct forms of formulation comprising the active agent are described herein - a solution · not in accordance with tire preseri! invention) and a suspension (In accordance with the present invention,! with superior characteristics compared to another composition formed as a get. The active agent formulated as a suspension is supenor compared to when the same active ingredient Is formulated as a ge! form in delivering the active at the posterior segment of eye, wmie towering the exposure in the front of the eye. increased levels of the active agent in the front of the eye limit ocuiar toierabiiity of topical drops containing the active. Therefore. reduced btoavailabiiiiy of the active agent at tire corneal or conjunctiva! surface, while maintaining adequate concentrations necessary to hind the relevant receptors at the target tissues and confer a therapeutic effect in the posterior segment of the eye, such as the choroid and the retina, are highly desirable and are the outcomes achieved from fhe specific embodiments described here.

[0010] The present invention relates to formulations and methods useful for treating pathological states that anse or are exacerbated hy ocuiar angiogenesis and vascular leakage, for example, in diabetic retinopathy [including background diabetic retinopathy, proitferallve diabetic retinopathy arid diabetic macular edem3): age-relaied macular degeneration (AMD) {including neovascuiar tweVexudative) AMO. dry AMO. and Geographic Atrophy): pathologic choroidal neovascularization (CNV) from any mechanism (i.e. high myopia, trauma, sickle cell disease: ocular histoplasmosis, angioid streaks, traumatic choroidal rupture, drusen of the optic nerve, and soma retina! dystrophies?; pathologic retinal neovascularization from any mechanism (is, sickle cell retmopathy. tales disease, ocular ischemic syndrome, carotid cavernous fistula, famiiiai exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic occlusive arteriolitis, hirdshot retinochoroidopathy, retinal vasculitis, sarcoidosis, or toxoplasmosis): uveitis: retina! vein occlusion (centra! or branch): ocular trauma; surgery induced edema: surgery induced neovascularization: cystoid macular edema, ocular ischemia: retinopathy of prematurity; Cc-3t:s disease: sickle cell retinopathy and/or neovascufar glaucoma. The formulation of the current invention lias, at least, one anti-angiogenic agent, anti-inflammatory ageni, or anti-vascular permeability agent for use in treating angiogenic ocular disorders.

[0011] According to embodiments of the invention, the active agent Is a kinase inhibitor of Formula II

[0012] The present invention provides a topical ocular formulation, comprising: a. an active agent of Formula ii:

ora pharmaceutically acceptable salt thereof, and b. pharmaceutically acceptable excipients: wherein fhe active agent or the pharmiioeuticaily acceptable salt is present m about Q. 1 % fo about 2.0% w/v such that the formulation forms a suspension.

[0013) In some embodiments of the current invention, (he formulation compr ises about 0.2¾ f¢:- about 1 % tromethamine. [0014] In some embodiments of the current invention, the formulation comprises a nornerne liquid polymer of the alkyl aryt polyether alcoixii type.

[0015] In somaembodiments of the current invention, the nonionic liquid polymer of the alkyl aryl polyether aicoho! type is tyioxapot.

[001 fi] in some embodiments of the current invention, the formulation comprises a hydrophilic non-ionic surfactant.

[0017] In some embodiments of the current invention, the hydrophilic non-ionic surfactant is poioxamer.

[001SJ In some embodiments of the current invention, the formulation comprises about 1 % to about 2% glycerin.

[0010] in some embodiments of the current invention, the formulation comprises about 0.6% tromethamine and abouf T% to about 2% glycerin.

[0020] In some embodiments of the current invention, the formulation further comprises a thickening agent.

[0021] tn someembodiments of the current invention, the thickening agent is hydroxy ethyl cellulose (HECt or hydroxy propyl methyl ceiiuiose (HPMC).

[0022] in some embodiments o<the current invention, the thickening agent Is HPMC ora sett thereof.

[0023] in some embodiments of the current invention, the thickening agent is carboxvmethyi ceiiuiose or a sett thereof. [0024] in some embodiments of the current invention, the phsrmsceutico'iy acceptable salt is a hydrochloride salt of compound of formula It, namely Compound·!;;

Com pound-Ι i.

[002$] The embodiments of the.current invenfiofoprovideformutaffoos. of .0,1%· :te .about 2.0% w/v of the active- agent of Formula (iii, or a pharmaceutically acceptable sait thereof tor exaPipie, Compound-!, in some embodiments, the concentration of Compound-! or its free base (fomnuta ii) in the formulations is 0.1% - about it.2%, about 0.2% - about 0.3%, about 0.3% - about 0.4%, about 0.4% - about 0.5%;. aboui 0.5% about 6.8%, about 0.6% - about 0.7%. about 0.7% - about 0.8%. about 0.8% -about 0.S%, about 0.9% - about 1,0%. or about 1.1 -2.0% w/v for topical administration. In some embodiments, the formulation comprises 0.1% fo about 1.039 w/v of the active agent or a pharmaceutically acceptabfe S3it thereof. In some embodiments, the formulation comprises about 1 0% to 2.0% w/v of the active agent or a pharmaceutically acceptable saft thereof. In some embodiments ttie formulations include 0.1 %, about 0.2%, about 0.3%, about 0.4%, about G.5%. about 0.6%, about 0,7%. about 0.8%, about 0.9%, about 1,0%, or 2.0% w/v of Compound-I or its free base {formula tl). In some embodiments, the formulation comprises 0.1%. about 0.2%, about 0.3%, about 0.4%, about 0.5%. about 0.6%, about 0.7%, about 0 8%. about 0.9%·. about 1.0%%. or 2 0% w/v oi the active agent or a pharmaceutically acceptable salt thereof, and about 0.6% w/v tromethamine, [0026] The formulation may include one or more solubilizing agents.

[0027] The formulation comprising 0.1%, aboui 0.2%. about 0.3%. about 0.4%. about 0.5%. about 0.6%, about 0.7%. about 0.8%, about 0 9%. about 1.0%. or 2.0’% w/v of Formula (It), or a pharmaeeuticaity acceptable sati thereof, for example. Compound-I. may include a solubilizing agent. The solubilizing agent in ths formulation may be eyclodextrin, for example, S-hybroxyprapyl-jf-cyciodextrin, methyi-ff-cyciodextrin, randomly meihylated-O-cyclodextrin. ethylated-p-cyciode-xtrin, trtacetyt-ft-eyclodextrin, peracetyiaied-h-cyctodextrin. carbo xymethyi-[>- eyefodexfrin. hydroxyetbyl -Jf-cycfo-dextrin, 2 hydroxy 3 (tnmethyfommonsofpropyl p eyclodextrin glucosy) ii eyclodextrin mafiosi I 3 eyclodextrin, sul fobutyt ether-h-eyciodextrin. brartchedTi-cyciodexfrln. bydroxypropyf-y-cyctlodexfrin. randomly methylated-..•-cyciodex-tnn. trin’isihyl-y-cyclociextrin, or combinations thereof, [0028] In additional embodiments, the formulation comprising 0.1%, about 0 2%, about 0 230, aboutG 4%, about 0.5%, about O 6%, about 0.7%, about 0.339, about 0.3%, about 1 0%. or 2.0% w/v of the active agent or a pharmaceutically -acceptable salt thereof, may include a buffer, for example, tromethamine. In one embodiment, the formulation comprising 0.1 %, about 0.2%. aboui 0.3%, about 0.4%, about 0.5%, about 0 6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, or 2.01½ w/v of the active agent or a pharrnaceuticaffy acceptable sail thereof, may irtclutfe about 0.3% - about 1.0% w/v tromethamine, and optionally may further include about 0,005% w/v benzalkonium chloride (BAK).

[0029] The formulation may have a pH value of about 4.5 to about 7.5 at or under about 40 X. in some embodiments, the pH value of the formulation is between about pH 5.0 to about 7.0 at or under about 40 "C In one embodiment the pH value of the formulation is about 6.0 at or under about 40 "C.

[0030] The current embodiments provide a formulation of Compound-! or its free base (formula I!) for use in accessing posterior segment of the eye ertd/or lor treating and/or ameliorating a posterior segment disease vascuiopafhic or inflammatory disease of the eye. selected from diabetic retinopathy (including background diabetic retinopathy, nrolif-erative diabetic retinopathy and diabetic macular edema); age-related macular desgeneralion -AMD) (Including neevas-cuiar (weVexudatve) AMD, dry AMD. and Geographic Atrophy), pathologic choroidal neovascularization (CNV) from any mechanism (/ a. high myopia, trauma, sickle cett disease; ocular histoplasmosis, angioid streaks, traumatic choroidal rupture, drusen of the optc nerve, and some retinal dystrophies): pathologic retinal neovascularization from any mechanism (/,0.. sickle ceil retinopathy, Eales disease, ocular Ischemic syndrome, carotid cavernous fistula, familial exudative vltreorefinopathy. hyperviscosity syndrome, idiopathic occlusive arierioiitis: birdshot retinochorotdopafhy, retinal vasculitis, sarcoidosis and toxoplasmosis). uveitis; retinal vein occlusion (centra! or branch); ocular trauma, surgery induced edema; surgery induced neovascularization; cysfold macular edema: ocular Ischemia; retinopathy of prematurity; Coat’s

disease: sidde ceil retinopathy and/or nsovascniar glaucoma.

[0031] in some embodiments, the exposure time of Compounb-i is between 1 and 90 days, in some embodiments, the dosage regimen involves severe! courses of topical ocuiar arimlnisfratfon of a formulation comprising Compound-I to a subjeci for between 1 and 90 days. For example, the dosage regimen involves once daily, twice daily, three times daily or four times daily administration of the formulation for between 1 and 90 days. For example, the dosage regimen involves once, twice, three times, -or four times administration of the formulation on alternate days (f.e.. on d:av 1. 3. 5. 7 etc.) for up to 90 days. For example, the dosage regimen involves art miniate ring once on day 1, onæ ot twice tin day 2 - day 30. For example, the dosage regimen involves administering once, twice, three times, or four times on day 1, followed by once daily lor 2 -90 days. For example, the dosage regimen involves administering once, twice, three times, four times on riay i, followed by once, twice, three times, or four times on alternate days {/.a., on day 1. 3, 5, 7 etc ) for up fo SO days. For example, one dosage regimen involves once per day or twice per day for 1,2,3,4, or 5 consecutive days. For twice or three daily dosage regimen, subjects receive topical ocular dose of a Compound-f formulation on days 1 and 4 approximately about 4, 6. or 8 hours apart. In another embodiment, subjects receive topical ocular doses of a Compound-! formulation approximately abcut4,6, or & hours apart for four consecutive days, in some embodiments, subjects receive one or two doses of topical ocuiar dose of Compound-1 formulation per day for 5 consecutive days, in yet other embodiments, subjects receive one or two doses of topical ocular dose of Compound-! formulation for 5--90 consecutive days. In soma embodiments, subjects receive one or two doses of topical ocular dose of Compound-! formulation for at least 25 consecutive days. In one embodiment, subjects receive one or two topical ocular doses for at feast'90 consecutive days or more. I'n one embodiment, the formulation is administered 1,2. 3, of 4 times daily on consecutive days or on alternate days in one embodiment, the formulation is administered once or twice daily on consecutive days or on alternate days, in one embodiment, fhe formutation containing about 0.1%. about 9.2%. about 0.3%, about 0.4%. about 0.5%, about 0.6%, about 0.790, about 0.8%. about 0.9%, about 1.0%, or about 2.0% w/v of the active ageni or a pharmaceufically acceptable salt thereof is administered twice daily on consecutive days or on alternate days, in one embodiment the formulation is administered to one eye or both eyes, [0032] For example, a formulation comprising about 2 mg/ml SID of Compound-! is administered to one eye or both eyes of a subject for between 1 and SO days, in some embodiments a formulation comprising about 3 rng/ntL BID of Compound-! is administered io one eye or both eyes of a subject for between 1 and SO days, fn some embodiments a formulation comprising about 3 mg/ml QD of Compound-! is administered to one eye or both eyes of a subject for between 1 and Wdays, in soma embodiments s formulation .comprising about 4 mg/ml SiD df Compound-f is administered to one eye of both eyes of a: subject for between "1 and '90 days., in some embodiments a for mulatfon comprising about 4 mg/ml QD of Compound-! is administered to one eye or both eyes of a subject for between 1 and 90 days in some embodiments a formulation comprising about 5 mg/ml SID of Compound-1 is administered to one eye or both eyes of a subject for between 1 and 90 days, in some embodiments a formulation comprising about 5 mg/mL QD of Compound-i is administered io one eye ot both eyes of a subject for between 1 and SO days, fn some embodiments 3 formulation comprising about 6 mg/ml BID of Compound-! is administered to one eye or both eyes of a subject for between 1 and 90 days. In some embodiments aformufation comprising about 6 mg/ml QD of Compound- i is administered to one eye or both eyes of a subject for between 1 and 90 days. The dosage regimen for between 1 and 90 days may he any of this regimens involving consecutive or sitemate days described m the paragraph above.

[0033] in some embodiments, the form uiaf Ion of Formula (il) or Compound-1 is administered to one eye or boih eyes of a subject For example, about 0.2 % - about 0.6% (w/v) of the compound of Formula (l·) or about 0.1% - 0.7 ·% fw/v) of Compound-! composing formulation of the current disclosure is administered once a day (QD) or twice a day (BID) io one eye or both eyes of a subject for between 1 and 90 days, in some embodiments, Formula (ii) compound or Compound-! is eomplexsd with a complexing agent, e.g, cyctocextrin (e.g.. hydroxypropyt-p-cyciodextrin (HP-fi-CD, KLEPTOSE© HP8) (%)) in ratio of about 1:8. in which about 2% -13 % (w/v) cycfodextrin (e. g., KlEPTOSE© HPB {%)} is added to the formulation. The formulation further composes about 0.1% - about 0.2% buffer, e.g.. 10 mM phosphate buffer The desired osmolality of the formulation is about 200 - about 300 mOsrn, achieved by adding quantity sufficient to achie ve the osmolality, with iasait, e.g.. sodium chloride. The pH of the formufation is about 6,0,

OETAllEG DESCRIPTION GF THE INVENTION

[0034] The materials, compounds, : compositions, .articles., and , methods described heroin may be understood more readily by reference io fhe following detailed description of specifte aspects of the disciosed subject matter and the Examples included therein. Before the present materials, compounds, compositions, adicies, devices, and methods are disclosed ano described, it is to be understood that the aspects described bsiow are not limited to specific synthetic methods or specific reagents, as such may vary. it. is also to be understood that the terminology used herein :s for fhe purpose of describing particular aspects only and is not intended to be limiting.

[0035] The present invention provides compositions or formutafions according to the ciaim 1 that contain an active agent for use in the treatment of ocuiar disorders caused by endothelial cel! proliferation, enhanced vascular permeability. inflammation, or angiogenesis The formulations of the invention are useful in preventing or inhibiting neovascularization and vascular leakage associated with such ocular uisoruers. in some coses, the formulations of the invention cause regression of neovascularization.

GerterO/ DefirififOrfS

[0036] In this specification and in Ihe claims thai follow, reference is made to a number of terms, which shall foe defined to have the following meanings. Aii percentages, ratios and proportions herein are by weight, unless otherwise specified. Ail temperatures are in degrees Ceisius ι/C) unless otherwise specified.

[0037] By “pharmaceutically acceptable" is meant a material Ihat is not blologicaffy or otherwise undesirable, r.e„ the material can be administered io an indivlduai along with the relevant active compound without causing clinically unao-ceptabie biological effects or interacting in a deieierious manner with any of the other components o' the pharmaceutical composition or formulation in which it Is contained.

[0038] A weight percent of a component, unless specifically stated to the contrary, is based on ihe total weight of the formulation or composition in which the component is included.

[0039] By "effective amount'' ss used herein means “an amount of one or more of the disclosed compounds, effective <it dosages and for periods of time necessary io achieve the desired or therapeutic result.'’ An effective amount may vary according to factors Known in the art, such as the disease state, age, sex, and weight of the human or animal being treated. Although partiouiar dosage regimes may be described in examples herein, a person skilled in the art would appreciate ihat the dosage regime may be altered to provide optimum theiepeuiic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation, in addition, the formulations of this disclosure can be administered as frequently as necessary to achieve a therapeutic amount, [0940] "Excipient" is used herein to include any other compound that may be contained in or combined with one or more of the disclosed inhibitors that is not a therapsuiscaiiy or biologicaiiy active compound. As such, an excipient should be pharmaceutically or biologically acceptable or retevarjt [for example, an excipient should generally be non-toxic to the subject). ''Excipient” includes a single such compound and is also intended to include a piurelity of excipients. For the purposes of the present disclosure the term "excipient" and "carrier" are used interchangeably throughout the description of.the present disclosure and said terms are defined herein as, "ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition." [0041] As used herein, by a "subject" is meant an individual Thus, the ’'subject" can include domesticated animats (e.g,. cats, dogs, etc.), livestock [e.g.. cattte, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig. etc.), and biids. "Subject" can also inctude a primate or a human [9042] By "reduce" or other forms of the word, such as "reducing'' or "reduction," is meant lowering of an event or icharacteristic (e.g . vascular leakage, or tissue swotting). It is understood that this is typically in relation to some standard or expected value, in other weres it is relative, but that it is not always necessary for {he standard or relative value to be referred re.

[0943] "he term "treat" or other forms of the word such as “treated” or "treatment" is used herein to mean that administration oi a compound of the present invention mitigates a disease or a disorder in a host artci/or reduces, inhibits, or eliminates a particular characteristic or event associated with a disorder (e.g.. vascular leakage).

[0044] insofar as the methods of the present invention are directed to preventing disorders, it is understood that the term "prevent" does no; require that the disease state be completely thwarted. Rather, css used herein, the term preventing refers to the ability of the skilled artisan to identify a population th3t is susceptible to disorders, such that administration of the compounds of the present invention may occur prior to onset of a disease. The term does not imply that the disease state .be completely avoided.

[0945] The term "amei lorating” or other forms of the word such ss "smetiora te" is used herein to mean that adtrt frustration of a therapeutic agent of the present invention mitigates one or more symptoms of a disease or a disorder in a host and/or reduces, inhibits, or etiminates a particular symptom associated with the disease or disorder prior io and/or post administration of the therapeutic agent.

[0046] The disclosed compounds effect vascular leakage or pathological neovascularization by inhibiting a receptor tyrosine kinase.

[0947] Throughout the description and claims of this specification the word "comprise" and other forms of the word, suctt as "comprising" arid "comprises," means inefuding but riot limited to. and is not intended to exclude, for example, other additives, or components [0048] As used In the description and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[9040] Optional" or “optiwraily" means that ihe subsequently described event dr eircumsishpe can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where ϋ does not.

[0050] The term ‘’about" refers to any minimal alteration in the concentration or amount of a therapeutic agent that does not change trie efficacy of tbe agent tn preparation of a formulation anti tn treatment of a disease or disorder For example, without hieing limiting, the concentration of a there poetic agent would be effective if the concentration is varied between 0.005% to 5.0¾ ¢-0 0005%). Ths terra "about" with respect to con centra tion range of the tberapeuilcfactive agents of the current invention also refers to any variation of a stated amount or range which would be an effective amount or range.

[0051] The term "halo”, as used,herein. Unless otherwise indicated, fedudes fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro ano bromo.

[0052] The ierm "alkyl, "as used herein, unless otherwise indicated, includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, Cf-6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl Include, butare not limited to, methyl, ethyl n-propyt i-propyt, n-butyi, s-butyt, t-butyl, n-peniyt, s-pentyl. and n-hexyf. In certain embodiments, a straight chain or branched cham alkyi has six or fewer carbon atoms in its backbone (e.g., C 5-Cf: for straight chain, C3-Cg for branched chain), and in another embodiment, a straight chain or branched chain alkyl has four or fewer carbon atoms. Likewise, cycloalkyis have from three to eight carbon atoms in their ring structure, and in other embodiments, cycioaikyis have five or Six carbons in ihe ring structure. Alkyi can be substituted by replacing hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, afkylcarbonyioxy. aryl-carbonyioxy, aikcxycarbonytoxy. aryioxycarbonyioxy, carooxytate. aikylcarbonyt, arylcarbonyl aikoxycarbonyi, amino-carbonyl, aikylaminocarbonyl, dialkylsminocarbonyl, alkyithiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano. amino (incfuding etkylamino, diaSkyiamino, arytamino, diarylamtno, and atkylaryiarninc·). acylarnino (including atkyicarbonyiammo, arylcarbcnylamino, carbamoyl and ureido), amidino, imino, sulfhydtyi. alkyithio. arylthicj, Ihkxar-boxylate, sutfates. alkylsuiflnyi. sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alky-taryi, or an aroma tin or heteroaromatic moiety Cycloalkyis can be further substituted, e.g . with the substituents described above. An "alkyiaryl” or an "aratkyi” moiety is an alkyi substituted with an aryl (e.g . phenyimethyi (benzyl)).

[0053] Tbs term “alkenyl," as used herein, unless otherwise indicated, includes unsaturated aliphatic groups analogous In length and possible substitution to Ihe alkyls described above, but that contain at least one double bond. For example, the term '’alkeny?' includes straight-chain alkenyl groups (e.g.. efhenyl propenyi, butenyl pentenyi, bexenyl, heptenyl. octenvt, nonemyi, decenyl), branched-chain alkenyl groups, cycloalkenyl (e g , aiicyelic·) groups (e (?., cydopropeny!. cyciopentenyl, cydobexenyl, cycloheptenyi. cyctooclenyl). alky! or alkenyl substituted cycloaikenyt groups, and cydeatkyl or cycioafkenyl substituted alkenyl groups. In certain embodiments, a straight chain or branched cham alkenyl group has six or fewer carbon atoms in its backbone {e.g.. C2-Cy for straight chain, for branched chain) Likewise, cyctealkenyt groups may have from three to eight carbon atoms in their ring structure, and in some embodiments, cycloalkerty! groups have five or six carbons in tbs ring structure. The term includes alkenyl groups containing iwo tn six carbon atoms. The term ‘'C3-C-3" includes alkenyl groups containing three to six carbon atoms. Alkenyl can be substituted by replacing hydrogen on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyi groups, alkynyl groups, halogens, hydroxyl, alkylcarbonytoxy, arylcarbonyloxy, alkexycarbo-nytoxy, aryioxycarbonyioxy. carboxylate. elkylcarbcnyl. arylcarbonyl, aikoxycarbonyi aminocarbonyl aikyfaminocarbo nyi, dialkylaminocarbonyl, alkyithiocarbonyl, alkoxyl, phosphate, phosphonato. phosphinato, cyano, amino (including aikyiarnirto. diatkyiamino. aiyiamino. diar/lamino, and alkylarytamino). acylarnino (including atkylcarbonylamino. aryl-carbonyiamino, carbamoyl and ureido), amidino, imino, sulfhydryi. a!kyithlo. arylthio, tblocarboxyiate. sulfates, aiky-suifi-nyl. sulfonato. sulfamoyl, sulfonamido, nitro, trifluoromethyf. cyano, azido, heterocyclyl alkyiaryi, or an aromatic or heleroarom atic moiety [0054] The term "alkynyl". as used herein, unless otherwise indicated, includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, ’’aSkynyl" includes straight-chain atkynyi groups (eg., eihynyl, prcpynyi. buiynyl pentynyi, hexynyf, heptynyl, ociynyl, nonynyl decynyl). branched-chaln aikyny! groups, and cyctoslkyt or cycloatkenyt substituted atkynyi groups. In certain embodiments, a straight chain or branched chain aikyny! group has six or fewer carbon atoms in its backbone (e.g.. C;v-Cp for straight chain, C3-C6 tor branched chain). The term "C2-C% includes aikyny! groups containing two to six carbon atoms. Tbe term ”CS-Cfi” includes alkynyl groups containing three to six carbon atoms Alkynyl can be substituted by replacing hydrogenen one or more hydrocarbon backbone carbon atoms. Such substituents can include, for exam ptew alkyi groups, alkynyl groups, halogens, hydroxyl alkylcarbonyloxy, aryfcarbonyloxy. sikoxycarbonytoxy. aryioxycarbonyioxy, carboxyiate, alkylcarbony!, arylcarbonyl, aikoxycarbonyi, aminocarbonyl, aikylaminocarbonyl, dialkyiaminocar-bonyl alkyithiocarbonyl. alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylarnino, dialkylarni-no. aryiam-no, dtaryfammo, and afkylarylamino), acylarnino (including aikylearbonytemino, arvlcarbonylamino,carbamoyl and ureido), amidino, imino, sulfhydryi. aikyltbte, arylthio. thioc-arboxyiate, sulfates, sikyisulfinyl sulfonato, sulfamoyl suiten amido, mtro·, tnffuoromethyl, cyano, azido, heterocyclyl, alkyiaryi, or art aromatic or heteroaromatic moiety.

[0055] The term "alkoxy,” as used herein, unless otherwise indicated, metudes O-aiky: groups wherein “atkyl" is as defined above, [0056] The term "aryl," as used herein, unless otherwise indicated, includes 5- end b-membered "unconiugated", or slngiis-rlng, aromatic groups that may include from zero io four heterooforos, os well as "conjugated", or rnuiticycfic, systems with at teas· one aromatic ring Examples of aryl groups include benzene, phenyl. pyrrole, furan, thiaphene, thiazole, isothiazoi©. imtdazois. triazoie. tetrazole, pyrazote, oxazole, isooxazoie, pyridine, pyrazins. pyridazina, and pyrimidine, end the like. Furthermore, the term “aryl" includes mutticyclic aryl groups, e.g·.. tricyclic. hityoiic, e.g.. naphthalene, berizoxazole. benzo diox azole, benzothiazole, benzoimidazoie, benzoihiophene, methylenedioxyphenyi, quinoline. isooijinoline, rtaphthyndine. indole, benzofuran, purine, benzofuran, deazapurine, oriodotizine Those aryl groups having heteroatoms in the ring structure may also be referred to 'aryl neierocycies", ’’heterocycies.’’ "hetero-aryls" or "heteroaromafics'' The aromatic ring can be substituted atone or more ring positions with such substituents as described above, as for example, halogen, hydroxy}, alkoxy, alkytoarbonyioxy. aryioarbonyloxy. atkoxycarbonyioxy. aryioxyoarbo-nyioxy. carboxylate. aikylcarbonyi, aikyiaminoeartonyi, aralkyiaminocarbonyl, aikertylaminoearbonyi. aikylcarbonyi. aryi-carbonyi. aratkyicarbonyl, aikenyicarbonyi. atkoxycarbonyt. aminooartionyi, atkyitbiocarbonyt, phosphate, phosphonato. phosphinato, cyano, ammo (including atkylamino, diaikylamino, aryiamino. diarvtamino, and aikyiaryiamino). acvfamino (including aikyicarbonyiamino, arytcarbonyiamino. carbamoyl and ureido), amidino, imino, suifhydryl, stkyithio, arvithio, thiocarboxylate, sulfates. atkyisutfinyl, sutfonafo, sulfamoyl, sulfonanndo, miro, triiiuoromeihyl, cyano, azido, heterocyctyi, alkyiaryi, or an aromatic or heteroaromaiic moiety Ary! groups can also be fused or bridged with alicychc or heterocyclic rings, which are not aromatic so as to form a muiticyctic system (e.g.. tetralm, methytenedioxyphsnyi}.

[0057] The term '4-10 membered heterocyclic," as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one er more heteroatoms each selected from O. S and N. wherein each heterocyclic group has from 4-10 atoms in iis ring system. Non -aromatic heterocyclic groups inctude groups having only 4 atoms in their ring system, but aromatic beterooycficgroups must.have at least 5 atoms in their ring system. An example of a 4 membered heterocyclic group is azeftdinyi (derived from azetidin©}. An example of a 5 membered heterocyclic group is thia/oiy! and an example of a 10 membered heterocyclic group is guinoiirtyf. Examples of non-aromatic heterocyclic groups are pyrroiiciinyi, tetrahydrofuranyi, tetrabydrothienyi. teirahydropyranyl. tetrabydrothiopyranyi, piperidine, morphoiino. thiomorphotino. thioxanyf, plperazinyi, azetidinyl, oxetanyf, thietanyf, homopiperidinyl, oxepanyl, thlepanyi. oxazepiriyl, diazepmyi, ihiazepinyi, 1,2,3,6-tetrahydropyridinyi. 2-pyrrolinyi, 3-pyrioiinyl, mdolinyl, 2H-pyranyi. 4H-pyra-nyi. dioxanyt, 1,3-dioxolanyl, pyrazolmyi, dithianyl, dithiolanyi, dihydropyranyi, dihydrothienyt, dihydrofuranyt, pyrazoiid-inyl. imidazoiinyf, irnidazotidinyl, 3-3zabicycio[3.1 OJbexanyt. 3-azabicycfo[4.1.0]heptanyi, 3H-indolyt and quinoilzinyi. Examples of aromatic heterocyclic groups are pyridinyt. iroidazoiyf. pyrimidinyf. oyrazotyi, iriazotyl. pyrazinyt. tetrazotyi, fury!, inieny!. isoxazolyt. thiazolyi, oxazolyi, isothiazotyf. pyrroiyt. quinofinyt, isoguinolinyi, indoiyi, benzimidazolyt. benzoin ranyt. cinnoltnyi, indazoiyi, inriolizinyf. phthalazinyi, pyriciaziny). friazinyl. isoindolyl. piendinyi, purinyt, oxadiazoiyi. thiadiazoiyt, furazanyf. benzefurazanyt. benzothiophenyl, benzothiazoiyf, benzoxazofyl, quinazotinyl, guinoxalinyf, naph-thyridinyi, and furapyndinyl. The foregoing groups, as denved from ihe compounds listed above, may be C-aftached or N-sttached where such is possible For instance a group derived from pyrrole ni3y be pynci-f-vi (N-a‘lached) or pyrrof-3-yi (C-attached). The ”4-10 membered heierocycfic" moiety can be substituted.

[0058] The phrase “pharmaceutically acceptable saft(sk’' as used hereifi. unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of Fortnuia (I) or (fit. The compounds of Formula (!) or (I!) thai are basic in nature are capable of forming a wide vaneiy of salts with various inorganic and organic acids. The acids that may be used io prepare pharmaceutically acceptable acid- addition saits of such basic compounds of Formula (f) or lit} are those that form non-toxic acid addition salts, i.e . salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydraiodide, nitrate, sulfate, bisuifate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, genfisinate. furnarate, giuconate, glucaronate, saccharate, formate, benzoate, glutamate, metbaoesuifonate, ethanesuifonate. benzersesuifonafe. p-toluenesulfooate and pamoate [i.e.. i,1-meihyiene-his-(2-hydroxy-3-rtaph-Shoate)] satis [0059] Those compounds of Formula (I) that are acidic In nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali meta! or alkaline earth metat salts and particularly, the sodium and potassium salts, in some embodiments, the sat; is an acid addition salt, e.g. HCI salt. [0060] Certain compounds of Formula (i) may have asymmetric centers and therefore exist in different enantiomeric forms. This invention relates to tne use of all optical isomers and stereoisomers of the compounds of Formula (I) and mixtures thereof. The compounds of Formula (!) may also exis; as E-'Z geometric Isomers or tautomers. This invention relates to the use of al! such geometric isomers and tautomers and mixtures thereof.

[0061] The subject Invention also includes isotopically-labeted compounds, and the pharmaceutically acceptabte salts thereof, which are identical to those recited in Formula (!}. bul for the· fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 1-C. 1;iC, 18O ^0, s5S. 13F. and 3l5Ci, respectively. Compounds of the present invention, conjugates thereof, and pharmaceutically acceptable salte of said compounds or of said conjugates which contain the aforementioned isotopes and/or other isotopes of other atoms are w-thin the scope of this invention. Certain tsotopicaliy-iabeied compounds of the present invention, for example those info which radioactive isotopes such as -’Η and 1 *C are incorporated, are usefi.it in drug and/or substrate tissue distribution assays. Tritiated, i.e., JH. and carbon-14, i.e.. 54C isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i e., -hi. can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo naif·fife or reduced dosage requirements and. hence, may be preferred in some circumstances, tsolcpicatly labeled compounds of Fomiutne {i) of ibis invention and esters or lipid ccniugates thereof can generally be prepared by carrying out the procedures disclosed m the Schemes and/or fn the Examples and Preparations befow, by substituting a readily available isotopicaiiv labeled reagent for 3 non·· isotopicafiy labeled reagent.

[0062] The term "kinase" refers to arty enzyme that catalyzes the addition oi phosphate groups to a protein residue: for exampte, senna and threonine kinases catalyze the addition of phosphate groups io serine and threonine residues [0063] The terms "VEGFR kinase," "VEGFR," refer fo any of the vascular endothelial growth factor receptors, [0064] The terms "VEGF signaling,'1 and "VEGF cascade" refer to both the upstream and downstream components of the VEGF signaling cascade.

[0065] The term "pharroaceuticaify acceptable” refers totne fact 1hat the carriei, diluent or excipient must be compatible with the other Ingredients of the formulation and not deleterious io the recipient thereof.

[0066] The terms "administration of a compound" or "administering a compound” refer to the act of providing a compound of the invention or pharrnaceuticai formulation to the subject in need of treatment.

[6067] The term "vascuiostasis" refers to the maintenance of the homeostatic vascular functioning leading to the norma! physiologic functioning.

[0068] The term "vasculostatic agents" refers to agents that seek to address conditions in which vascuiostasis is compromised by preventing the loss of or restoring or maintaining vascuiostasis.

[0669] In the current disclosure "composition” and ’’formulaiion” are used interchangeably and refer to the conventional understanding, as known in the art. of a composition or formulation [0070] Tiie current inveriiion relates io an ophthalmic formulation. In some embodiments, the ophthalmic formulation of the current invention ts a gef formutation or a semi-gel formulation, or both [0071] "Go!" according to -he current invention Is a semi-solid dosage form of the current invention, containing sus pended particles. A semisoild is not oourabfe; it dees not flow or conform to its containerat room temperature. A semisofid does not flow at icw shear stress and generally exhibits piastic flow behavior, A colloidal dispersion is a system m which particles of coiloida! dimension {i.e.. typically between 1 nm and t pm) are distributed uniformly throughout a liquid. [0072] in some embodiments, “gel" is a semisoiid system consisting either ot suspensions of smail inorganic particles or of organic molecules interpenetrated by a liquid "Gels” are classed either as smgie-phase or two-phase systems "Gels" afso consist of a rnesopha&e, or state of matter intermediate between a liquid and a solid that represents a partially ordered structure, which is the state for the active agents in the "Gei Drop" of the current embodiments A two-phase gel consists of a network of smaii discrete particles. In a two phase system, the gei moss sometimes is referred to os magma {e.g., Bentonite Magma) if fhe particfe size of the suspended material is large. Both geis and magmas are thixotropic, forming serrosolids on standing and becoming liquid on agitation. The semisoiid formulations should be shaken before administration to ensure homogeneity and should be so labeled (see Suspensions). Single-phase gels consist of organic macromoiecuies uniformly distributed throughout a liquid in such a manner that no apparent boundaries exist between the dispersed macromolecuies and the liquid. Single phase gels may also consist of organic low moiecuiar weight (LMW) molecules where the component responsible tor gelation is the actuai active ingredient These so called “LMW hydrogels" are different from traditional gelators of water such as high moiecuiar weight synthetic polymers, polysaccharides, and proteins. High moiecuiar weight, gelators are highly ordered and um-directional due to hydrogen bonding whereas the forces governing LMW hydrogels are largely non-direefionaf van der Waafs forces (hydrophobic) interactions, in practice LMW hydrogels are observed as highiy anisotropic: {typically fibrillar) structures that propagate-throughout the liquid yielding a physically branched or entangled network. The geis can thus be non-ordered to slightly ordered showing some birefringence, liquid crystal character. Gels ere administered topically or, after shaking, in the form of a nydrogel as an eye drop.

[0673] The semisoiid "gel" according to the current invention is a semisofid per USP definitions and literature referenced therein, Tne semisolid formulation apparent viscosity increases with concentration. The ciinicai dosage strength of the current formulation ranges from a low strength of <1 mg/mL (0,1 %) to a high strength of <6 mg/ml (0.6%). Low strength doses are least viscous arid fsli tinder the category of a ’’solution,” whereas higher strengths arc more viscous and fit the definition of a gei.

[6074] "Jelly" according to the current invention is a class of gels, which are semisoiid systems that consist of suspensions made up either small inorganic particles or large organic molecules interpenetrated by a liquid, in which the structural coherent matrix contains a high portion of liquid. usually water [0675] "Solution” is a clear, homogeneous liquid dosage form teat contains one or more ohemicai substances dissolved in a solvent or mixture of mutuaffy miscible solvents. A solution Is a liquid preparation that contains one or more dissolved chemical substances in s suitable solvent or mixture of mutually miscible solvents. Because molecules of a drug substance tn solution are unifamnly dispersed, the use of solutions as dosage forms generally provides assurance of uniform dosage upon administration and good accuracy when the solution is diluted or otherwise mixed.

[0076] "LiCfmd" is a dosage form consisting of a pure chemical in its liquid state. A liquid is pourable: if flows and confftrnns to its container al room temperature. Liquids display Newtonian or pseudoplasiic flow behavior [0077] "Suspension" according to the current invention Is a liquid dosage form that contains solid particles dispersed in a liquid vehicle, [0078] The compounds of the invention: are formulated into therapeutic formulations as natura! orsait forms. Pharmaceutically acceptable non-toxic sails include the case addition salts [formed with free carboxyl or other anionic groups) which are derived from inorganic bases such as, for example, «sodium, potassium, ammonium, calcium, or ferric hydroxides.. and such organic bases as isopropylamme, irimeihyiamme, 2-ethylaminoethanol, histidine, procaine, and the like. Such sails are formed as acid addition salts with any free cationic groups and generaffy are formed with inorganic acids such as, for example, hydrochloric, sulfuric, or phosphoric acids, or organic acids such as acetic, citric, p-toiuenesuifonic, methane sulfonic acid, oxalic, tartaric, manuelle. and the like. Salts of the invention include amine safts formed by the protonation of an ammo group with inorganic acids such as hydrochloric acid, hydtobromic add, hydroiodic acid, suffunc acid, phosphoric acid, and the ilke. Saits of the invention also include amice salts formed by the profanation of an amino group with suitable organic acids, such as p-toluenesuifonic acid, acetic acid, and the like. Additional excipients which are contemplated for use in the practice of the present invention are those avaiiabfe fo those of ordinary skill in the art. for example, those found in the United States Pharmacopoeia Vol. XXi! arid National Formulary Voi. XVH. U.S Pharmacopoeia Convention. Inc., Rockville. Mrf (1989).

[0079] The present invention provides a topical ocuiar formulation, comprising: a. an active agent of Formula It:

or a pnarrnaceuiicatly acceptable salt thereof, and b. phamtacéufieaiiy acceptable excipients;

Wherein the active agent or the pharmaceuticaliy acceptable salt ispreseht in about 0; 1 % to about 2.0% w/v such that ihe formulation forms a suspension.

[0080] A compound of fhe current inven-ion Is 3-(i4-bromo-2.6-dif!uorophenyi)tnethoxyj -5-[(1(4-( i-pyrro!idi-nyl)butyi]amino]c3rbonyl]amino]-4-isothi3zo!ecarboxamide hydrochloride, of mofooular formula: C20H2iBrF2N5O3S HCI, moiecuiar weight. 668.86 g/moi, and with the property that the molecule does not contain an asymmetric center and is not chiral. A compound of the current invention is represented by Compound-!:

(Compound-I).

[0081] The Compound-i of the current invention isen inhibitor of the tyrosine kinase activity cf VEGFR-2, which blocks VEGF-stimuiatsd auto-phosphoryiation of this receptor as well as endothelial ceil proliferation It ts selective (>500x) relative to the concentration required to inhibit -be epidermal growth factor receptor (EGFP) .and ths insulin receptor (IR) tyrosine kinases. Compound-! is described in US Patent No 6,235,764

Genera/ Properties [0082] Compound-I of the present invention has the characteristics as shown in Table 1. The embodiments provide three formulations of Compound-I or its free base-the Formula it compound.

Tabie 1 A: General Properties of Compound-! Drug Substance

[0083] The eempositioricrfThe Gempouttd-! formuiaiions are listed irt Table IB. Tbe formulation matertais are: listed fe Table 1C.

Table 18; Compound-! formulations: Gel Drop, suspension, and solution.

Formulation Forms Composition

Ophlhafmic get drops fnot ;n accordance with the present 6.05% Sodium Phosphate. Monobasic. Monohydrste invention) 1.0-2.0% Glycerin with or without 0.005% Benzalkonium Chloride, NF (BAK) pH -6.0-7,0

Tns-bassd suspensions 0.6% Tromethamine. DSP (Tris)

1.0-2.0% Glycerin, USP with or without 0.095% Benzalkonium Chloride. NF (BAK) pH -6.0-7.0

(continued)

Formulation Forms Composition

Cyclo dextrin -based solutions (not in accordant® with th& 1 % to 20% hydro xypropyf- 8-cyckxiextnn (HP -β-CD. ore.sen/ mvenf/oo) KLEPTOSE© HP8) 0.1% to 0.9% sodium chloride pH -6.0-7.G or 1% to 20% sutfobuiyiethsr-F-cyeiodsxtnn (SBE-h-CD, CAPTISOL®} with or without 0.122% Tromethamine (Trist 0,1-0.2% sodium phosphate, dibasic, anhydrous Q%-0.6% sodium chloride pH -6.0-7,0 or 1% to 20% HP-i'.-CDfKLEPTOSE© HPS or KLEPTOSE© HP}

0.1-0 2% sodium phosphate, dibasic, anhydrous 0.50%-0.6% sodium chloride pH -6.0-7.G

Tabte 1C: Fonmuiation materials

Ophthalmic Sofudops {not in accordance with the pfoseot iovention) [0084] Formuiations of Compound-S and/or its free base (Formula H compound), may be formed as a solution with viscosity similar to water. The solution includes pharmaceutically acceptable agontstexcipients, for example, without being limliing. cyciodextrin. The solution thus formed is clear arid colorless solution, suitable lor topical administration fc? the eye.

[0085] The solutions reduce anterior segment exposure of the active agent; thereby they allow increased concentration of the active agent in the sotuiion and increased frequency of delivery, thus, promoting maintained high concentration of ihe active agent in the posterior segment of the eye.

[0086] The solutions comprise about 0 C05% to about 5.0% w/v of the active agent of Formulae 1, or a phan-naceuficaiiy acceptable saii thersiof, for example, Compound-;. The concentration of Compound-! or its free base {formula fit in Ute solutions may be about 0,605% - about C.01%, about 0.01% - about 0.05%, about 0.05% - about 0.1%. about 0.1% -about 0.2%, about 0.2% - about 0.3%, about 0.3% - about 0.4%. about 0.4% - about 0.5%.. about 0.5% - about 0,6%, about 0.6% - about 0.7%, about 0.7% - about 0.8%, about 0.8% - about 0.9%, about 0,9% - about J.0%, about 1.0 -about 2.0%, about 2.0 - about 3,0%, about 3.0 - about 4,0%. or about 4.0 - about 5.0% w/v for topicai administration. In some embodiment, the solutions include about 0.005%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%. about 0.6%. about 0 7% about 0.8%, abous 0.9%. about 1 0%.about2.Q%, about 3.0%. about 4.0%, or about 5.0% w/v of Compound-! or its free base (formula Ii),

[0087] The formulation may comprise cyciodextnn for improving solubility of Compound-!. Cyctodextnn, an oligosaccharide made up of six fo eight dextrose units joined through one or four bonds increases sotobiiity of active agents that have poor or low solubility in water or afji.isoi.is solutions (eg, in PBS buffer) Cyclodextrins form hydrophilic complexes with hydrophobic active agents.

[0088] One or more cyclodextrins may be used in the solution. Non-limtiing examples of cyclodextrins for use in formulation are, for example; 2-hydroxypropyl-b-cyctodextrir·, melbyl-p-cyoiodextrin, randomly methyiated-h-cyclodex-irin, elhytotect-p-cyoiodextrirs, Iriacetyi-fFcyciodexirin, peraeeiytated-fi-cyclodextnn, carboxytnethyi-li-cydodextfin. by-droxyethyi -b-eyciodextnn, 2-hydroxy-3'(frimethylammonio)propyf-iS-cyc!ocfex?rin. gfucosyi -[i-cyctodextnn, maltosyl-JF cyclodextnn. suifohuiyf eiher-[’,-cycfodsxtrin, branched-it-cyclodextnn, hydraxypropyi-j-cyciodext-tn, randomly meihyi-sted-y-oyciodexirin. trimethyl-y-cyctodextrin, or combinations thereof.

[0889] Tbe solution of Formula ii compound or Compound-! comprising eyclodextrin may be a clear and colorless solution and have a viscosity similar to water. A solution comprising Compound-I and one or more cyciodextrin for topical application is topically applied io the eye.

[0090] The ophthaimlc solution comprising eyclodextrin may include pharmaceutical excipients chosen at or below concentrations optima) tor ophthalmic solution. The excipients are. for example, benzalkonium chloride (BAK) and NaCi. The ophthalmic solution may comprise about 0.001 - about 0.005% w/v Benzalkonium chloride {BAK). The BAK amount varies depending on the freed of tbe invention [0891] Tbe ophthalmic solution comprises, for example, without being limiting, about 0,005% - 5.0% Compound-! or its free base, about 2 - about 26% cyciodextrin, e.g,. without being limiting, Hydroxypropyl-ji-cyctodextrin (HPbCD) or methytcyctodexirin (KLEPTOSE© HPB), and/or sulfobutyl etbi-r-p-cyeiodextnn (CAPT1SOL·?)), about 0 1 - about 0 7% sail, e.g., without being limiting. NaCi, and/or about 0,065% ofan antimicrobial agent, for example, without being timiting, Benzaikonlum chloride (BAK). The formulation comprises Compound-! or its free base to cyciodextrin ratio 1:2, 1:3, 1:4, 1 5, 1:6, 1:7, 1:8, 19. 140, or between 1:10 and 120. The ophihalmic solution comprising cyciodextrin may further comprise tromethamine (else known as Tns, Trisf Hydroxy meihyijarniriomeihane. or Ths butler j The aphitraimic solution rnay comprise about 1% Tris.

[0092] Ophthalmic solutions include, for example, without being limiting: about 0 3% - about 5 0% Compound-! (about 3 mg/rnL - aboui 50.0 rog/roL), about 0.05% sodium phosphate monobasic rrtenohydraie. about 2% glycerin; about 0.4% Compound-!, about 7% ί-lPttCD, about 0.7% NaCI. aboui 0.005% BAK: about 0.4% Compound-!, aboui 4% HP;1CQ, about 0 7% NaCi, about 0 005% BAK. about C 4% Compound-I, about 7% KPftCD. about 1% tromethamine, a bout 0 4% NaCI. about 0.005% BAK; and about 0.63:, Compound-!, about 7% HPjiCD, about 0,7% NaCi, about 0.00556 BAK. For Compound-! of between aboui 0 005%, to about 6.0% concentrations, cyciodextrin is present al a corresponding molar ratio, [0033] Additional ophthalmic solutions include, for example, without being limiting: about 0.4% Formule tl compound (frae base), aboui 7.15%, HP|5CD, about 0.7% NaCI; about 0.1 % Poimuia tl compound (free base), about 1.79% HPpCD, about t).85%> NaCI: about 0,2%o Formula 51 compound (free base), about 3 57% HPOCD. about 0.8% NaCI; about 0 6% Formula ii compound (free base), about 10.72% HP;'.CD, aboui 0 6% NaCI: about 0.4% Formula I! compound (free base), about 8.4116 HPpCD, about 0.65% NaCI: about 0.4% Compound-I, about 10.51 HPJ5CD, about 0.65% NaCi; about 0.4% Formula II compound (free base), about 10.51% HP[5CD, about 0.15% NaCi, aboui 1.0% tromethamine (Tris), and/or aboui 0.1% Formula I! compound (free base), about 2.63% HPj'.CD, aboui 0 8% NsCi; about 0 6% Compound-5 (as free base), about 15 77% HPpCD, about 0.37% NaCi. For Formula 1! of between about 0,005% to about 5:0% concentrations, cyciodextrin is present at a corresponding moiar ratio.

[0894] Ttie ophthalmic solutions of Compound-! may include between about 1 0% - about 26% cyciodextrin. For example, without being limiting, tbe Compound-! formulations include about 2.0% - about 3.0% HPpCD. about 3.0% -about 5 0% HPpCD, about 5.0% - about. 10% HP[5CD, or about 10% - about 25% HPI3CD.

[0895] The ophthaimlc solutions oi Compound-! or its free base may be i'otmufated as. for example, without being limiting: about 8 41% KLEPTOSEE; HPB and about 0.142% phosphate, about 8.9% KLEPTOSEE; HPE5 and about 0.142% phosphate: snout 4.8851 CAPTfSOL© and about 0.142 phosphate; and/or about 4.88% CAPTISOL© and about 0.122% phosphate.

[0896] The ophthalmic solutions comprising cyclodextrins may be clear and ceiodeas, and may be extremely viscous) moderately viscous, or nave viscosity similar to water.

[0097] The ophthalmic solution may have a pH value of about 4.5 to about 7.5 at or under about 40 "C

[9098] For example, the ophthaimlc solution has a pH value of about S O at or under about 40“C.

[0999] Tbe ophthalmic solution may nave a pH value of aboui 5.0 to about 7.0 at or under about 40 °C.

[0100] Tbe ophthalmic solutions of ihe present disclosure contain various additives incorporated ordinarily, such as buffering agents (e.g., phosphate buffers, borate buffers, citrate buffers, tartrate buffers, acetate buffers, amino acids, sodium acetate, sodium citrate and the like), tonicity agents (e.g.. saccharides such as sorbitoi. glucose and mannitol, poiyhydric sicohols such as glycerin, concentrated glycerin. PEG and Propylene glycol, satis such as sodium chloride, etc,}, preservatives or antiseptics (e.g., Benzalkonium chloride, Benzatkonium chloride, P-oxybenzoates such as Methyl p-oxybenzoate or Ethyl p-oxybenzoate. Benzyl alcohol. Phenethyl alcohol. Sorbic acid or its salt. Thimerosal, Cbiorob-ufanof, etc.), solubitiztng t-ids or stabilizing agents (e.g., waurr-soluble polymers such as polyvinyl pyrrolidone. surfactants such as tyioxapol, pc iy sc.· "hates. eic.), pH modifiers (e.g.. Hydrochloric acid. Acetic acid. Phosphoric acid, Sodium hydroxide, Potassium hydroxide. Ammonium hydroxide and the tike), thickening agents (e.g., HEC, Hydroxypropy I cellulose, Methyl cellulose. HPMC. Garboxyroethyi cellulose and their salts}, chelating agents (e.g., sodium edetate. sodium ctrate condensed sodium phosphate etc.}.

[0101] The ophthalmic soiutions comprising cyctodexirin further comprise additionaf excipients, for exampie, without being limiting, about 0.6% - about 3% surfactant and emulsifier, for example, without being limiting, polysorhate SO or equivalent excipients thereof; about 0 05 - aixsuf 0.4¾ nonionic liquid polymer of the alky! aryl polyether alcohol type, for example, without being limiting iyioxapoi; and,for aboui 0,05% - about 0.6% hydrophilic non-ionic surfactant for example, without being limiting, poioxamer. such as poioxamer 407.

Cooeenirafto/i to Various Ocular Tlssueo-Oa/ivered as an Ophthalmic: Solution (not in accordance with the present invention) [0102] The ocuiar sotution comprising cyctodexirin improves bloavailabilliy of Ihe active agents of the current invention at the posterior segment of the eye. Without being bound by theory, (tie formulation comprising cyclodextrin may form a dear and colorless solution, which towers corneal exposure- cl the active agent, for example, exposure of Corf-pound-1, by about 5-1-5 fold compared to fhe corneal exposure to with an equimolar Gei Drop formulation.

[01 δ3] Without being bound by theory, an ophthalmic solution comprising cycfodextrin may increase the therapeutic index of Compound-! during topicai ocular administration. Upon administration, the hydrophilic complex oi cveiodextrin-Compound-I is pharmacologically inert at the cornea. Without being bound by theory, the cyciodextrin-Compound-l complex may increase corneal loierabliity of Compound-! Withoui being bound hy theory, spontaneous dissociation of cyciodextrin from Compound-! at ihe peripheral vasculature may increase bioavailability si the target tissue, e.g.. ai the choroid or retina.

[01C4] Uniike other formulations of Compound-!, which may contribute to comeal toxicity, the cyctodexfrin-based ophthatroic solution comprising similar concentration of Compound-I lower corneal exposures and. thereby increase fhe therapeutic index and corresponding benefits io patients. The use of cyclodextrin-based solution of Compound-! may provide approximately 10x reduction in cornea! exposure, as compared to equimolar concentrations of Gei Drop. The cyclodexirin-based solution of Compound-I may reduce corneal exposure of Compound-! by 5x. 20x. 30x. 40x, or 5f)x, For example. l-QOdays or 3-9 months of fopica! ocular dosing of about 0.005% - about 5.0¾ Compound-I as a cyctodexlrin-based solution dees not have any adverse or toxic effect at the cornea, choroid, and/or the retina. For example, 1-90 days of topical ocular dosing of about 0.6% - about 5.0% Compound-! as a cyctodextrin-bssed solution does not have any adverse or toxic effect at the cornea, choroid, and/or the retina.

[0105] The towering of die corneal exposure is correlated with increasing bioavaifability and therapeutic index of the active agent at the posterior segment, for exampte. ai the retina or choroid, of ihe eye. For exampte. no toxic effect attributable to the active agent or a suitable carrier is observed io the cornea or other parts of ihe eye when about 0.1 % - about 5.0% Compound-! formutation comprising cyciodextrin is administered topically administered to the eye for al teas! 30 days or more ill an 60 days.

[0106] When a formulation comprising about 0 4% -about 4 mg/mL'i of Compound-! or its free b3se. and cyciodextrin. Wheh administered topically fo the eye, the centra! choroid concentration may be between about 0 2 μΜ - about 0.9 μΜ, centra! retina concentration of the active agent may be between about 0 02 μΜ - about (5 4 j.-.fvl. aqueous humor concentration of the active agent may be about 0 003 μ.Μ - about C OOS μ.Μ, and corneal concentration of the active agent may be between δ μΜ - 30 μ M. The cyciodextrin used in the formutation is. for example, without being limiting example, KLEPT OSE® HP3 or CAPTtSOL®.

[0107] A cyctodsxtrin-basod solution of Compound-! or its free base may increase the bioavailabiiity of the active agent ai the central choroid and the central retina, while reducing concentration at the cornea. Topical delivery of Compound-! ar its free base formulated m the presence of cyctodexirin may reduce the corneal concentration by about 5 - about 15 fold over the corneal concentration of equimolar Ge! Drop.

[0108] Without being bound by theory, the combined effects of decreasing cornea! drug exposure so as to avoid poor ocuiartoierabifity while increasing posterior segment btoavailabifityfoay increase théiherapéirfié index and corresponding benefits to patients.

[0109] The exposure urne oi Compound-! may be between 1 and SO days Tire dosage regimen may involve several courses of topical ocular administration of a formulation comprising Compound-! to a subject for between 1 and SO days. For example, the dosage regimen involves once daily, twice daily, three times daily or four limes daily administration of the formulation for between 1 and 90 days. For example, the dosage regimen involves once, twice, three times, or four times administration of the formulaiion on alternate days ¢/ e . on day 1.3. 5, 7 eic.) for up to SO days. For example, ihe dosage regimen involves administering once on day 1, once or twice on day 2 - day 90. For exampte. the dosage regimen involves administering once, twice, three times, or four times on day 1, followed by once dally for 2-30 bays. For example, the dosage regimen involves administenng once, twice, three times, four times on day 1. followed by ones, twice, three times, or four Jimes on alternate days (/e . on day 1.3.5 7 eic.) for up to 90 days. For example, one dosage regimen involves once per day or twice per day for 1. 2, 3, 4, or 5 consecutive days. For twice or three daily dosage regimen, subjects receive topical ocular dose of a Compound-! formulation on days 1 and 4 approximately about 4.6, or 8 hours apart, in one example, subjects receive topical ocular doses of a Compound-! formulation approximately about 4. 6. or 8 hours apart for four consecutive days, in one example, subjects receive one or two doses of topical ocular dose of Compound-! formufation per day for 5 consecutive days, in yet other examples, subjects receive one or two doses of topical ocular dose oi' Compound·! formulation for 5-90 consecutive days. Subjects may rsceive one or two doses of topicai ocular dose of Compound-! formulation for at ieast 25 consecutive days. Subjects may receive one or two topical ocular doses for at ieast 90 consecutive days or more, [0110] For example, a formulation comprising about 2 mg/mL BSD of Compound-f is administered to one eye or both eyes of a subject for between 1 and 90 days. A formulation composing about 3 mg/mL BID of Compound-! may be administered to one eye or both eyes of a subject for between 1 and S3 days A formulation comprising about 3 mg/mL QD of Compound·! may be administered to one eye or both eyes of a subject for between 1 ano 90 days. A formuiation comprising about 4 mg/mL BID of Compound-! may be administered to one eye or both eyes of a subject for between 1 and 90 days A formulation comprising about 4 rng/mL QD of Compound-! may be administered to one eye or both eyes of a subject for between 1 and 90 days. A formutation composing about 5 mg,'mb BtD of Compound-1 may be administered to one eye or both eyes of a subject for between 1 and 90 days. A formulation comprising about 5 rng/mL QD oi Compound ) may be administered to one eye or both eyes of a subject for between 1 and 90 days A formulation comprising about 6 mg/ml BID of Compound-! may be administered io one eye or boih eyes of a subject lor between 1 and SO days. A formulation comprising about 6 mg/mL QD of Compound-! may be administered to one eye or both eyes of a subject for between ! and 99 days. The dosage regimen forbetwean 1 and 99 days may be any of the regimens involving consecutive or alternate days described tn the paragraph above.

[0111] Cyciodextrin-fcased solutions containing hydroxypropyl-beta-cycfodextrin (hiP-|i-C,D, KLEFTOSE© HFB) or CAPTiSOL© that are welt tolerated when administered topically tor 3(5 - 90 days or tot 4 - 3 months, tn some examples, once or twice daily administration of at about 0 005% - about 5.0% w/v Compound-ior Its free base in a solution containing about 1.9% - about 25% HP-[1-CD or CAPTiSOL® is well tolerated by the subject.

[0112] The formulation of Formula (it) or Compound-l may be administered to one eye or both eyes of a subject. For example, about 0.2 % - about 0,6% (w/v) of the compound of Formula (II) or about 0.1% - 0.7 % (w/v) of Compound-l comprising formulation of the current disclosure is administered once a day (QD) or twice a day (BID) to one eye or both eyes of a subject for between 1 and 90 days. Formula (It) compound or Compound-! may be comptexed with a comptexing agent, e.g., cyctodextnn (e.g . KlEPTOSE® HFB (%)> m ratio of shout 1:3. m which about 2% -13 % (w/v) cyclodexirin (e.g.. KLEPTOSE® HPS (%)) is added tr; the iorrnui3tion. The formulation further comprises about 0.1 % about 0 2% buffer, e.g., 10 mM phosphate buffer. The desired osmolality of the formulation is about 20G - about 300 mOsm, achieved by adding quantity sufficient to achieve the osmotuiity with a salt, e.g.. sodium chforide. The pH of the formulation is about 5.0 at or under about 40 'C. The dosage regimen for between 1 and 90 days may be any of the regimens involving consecutive or alternate days described in the paragraph above.

Ophthalmic Suspensions [0113] Ttie current embodiments provide suspensions of Compound-l including the compound and pharmaceutically acceptable excipients. For example. Compound-l suspensions Include, without being limiting, buffering agents, acids 3 bases, for example, without being limiting, HC! and NaOH. in one embodiment, suspensions of Compound-i or its free-base include buffering agent, lor example, without being limiting tromethamine (Tris). The tromethamine-based suspension oi Formula i! compound or Compound-! is useful for topicai administration to the eye [0114] The suspensions of the invention comprise 0.1 % to 2.0% w/v of an active agent of Formula ill), or a pharmaceutically acceptable sail thereof, for example, Compound-i. The concentration of Compound-! or its free base (formula ii) io the suspensions is 0.1% - about 0.2%, about 0.2% - about 0,3%. about 0.3% - about 0.4%. about 0.4% - about 0.5%, about 0,5% - about 0.6%, about 0.3% - about 0.7%. about 0.7% - about 0 S%, about 0.8% - about 0.9%, about 0.9% - about 1.0%. or about 1.0 - 2.0% w/v for topicai administration, in some embodiments, the suspensions include 0.1 %, about 0.2%. about 0.3%. about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%?, about 0.9%. about 1,0%, or 2.0% w/v of Compound-f or its free base (formula II!.

[0115] The ophthalmic suspensions may contain various additives incorporated ordinarily, such as buffermg agents {e.g., phosphate buffers, borate buffers, citrate buffers, tartrate buffers, acetate buffers, amino acids, sodium acetate, sodium citrate and the like), tonicity agents (a g , saccharides such as sorbitoi, giucose and mannitol, polyhydric alcohols such as ofyeenn. concentrated glycerin. PEG and propylene glycol, satis such as sodium chloride), preservatives or antiseptics (e.g., benzalkonium chloride, benzalkonium chloride, P-oxybenzoatos such as methyl p-oxybenzoate or ethyl p-oxybenzoate. Benzyl alcohol, phenefbyi alcohol. Sorbic acid or its sail, Thimerosal. Chtorobutanot and the itke), sol-ubiffzins aids or stabilizing agen-3 (e.g., cyclodextrins and their derivative, water--soluble polymers such ars polyvinyl pyrrolidone. surfactants such as tyioxapoi. polysorbates). pH modifiers (e g hydrochloric acid, acetic acid, phosphoric scid, sodium hydroxids, potassium hydroxide, ammonium hydroxide and the like), thickening agents (e.g.. HEC, hydrox-ypfopyl ceiiuiose, methyl cellulose, HPFvtC, carboxymethy! cellulose end ihelr sails), chelatinp agents i&.g.. eodium edetate. sodium citrate, condensed sodium phosphate) and ths; like [0116] The ophthaimio suspension of ihe cutreni invention includes pharmaceutical excipients chosen at or beiow concentrations optima! for ophthalmic solution. The excipients of tne current Invention metode, for example, without being limiting, sodium phosphate monohydrate. glycerin. and benzalkonium chtoride (BAK).

[0117] to some embodimen-s, 0 1%, about 0.2%. about 0 3%, about 0 4%. about 0.5%, about0.6%, about 0.7%, about 0.876, aboui 0.9%, about 1.0%, or 2.0% w/v of Formula til), or a pharmaceutically acceptabte salt thereof, for example, Compound-i, is an aqueous tromeihamme solution. Tbe tromethamine-based suspension of Compound-! or its free base includes additional buffers and excipients, for example, without being limiting,..phosphate buffer. The suspensions prepared in about 0,2% - about l .0% Tris may further comprise one or more surfactant and emulsifier, for example, without being limiting, potysorbate 80 or equivalent excipients thereof, one or more nonionic liquid polymer of the alkyl aryl pofyether alcohol type, for example, without being limiting iyloxapoi; and/or one or more hydrophilic non-tonic surfactant, for example, without being limiting, potoxamer, such as potoxamer 407 [0118] Tbe present disclosure provides suspensions of the agents of the current Invention formulated in the presence of excipients such as, without being limiting, Povidone, poiysorbate SO (PS80), polyethylene glycol (PEG)400,: tyfoxapoi, poloxamer. glycerin, and BAK in 3 Tris buffer.

[0119] In one embodiment the suspension of Compound-! or rts free base comprises aboui 0 1 - 0.5%. phosphate buffer, to some embodiments, the pH of the tromethamine-based suspension is between pH 4-7, for example, pH 8,0, tn some embodiments, the suspensions prepared in T ris further comprise aboui 0 5%> - about 2% polysorbate 80. about 0.05 - ebout 8.2% tyioxapoi. and/or aboui 0.05%, - aboui 0,4% poloxamer 407.

[0120] to some such embodiments, ihe suspensions of ihe invention further comprise about 0.01 - about 1 %, or about 1 - about 2.0% w/v glycerin. In a specific embodiment, ihe suspensions comprise aboui 2% w/v glycerin.

[0121] in some embodiments, the suspensions of the invention further compose about 0.001- about 0.005% w/v Benzalkonium chloride (BAK). The BAK amount may be varied depending on any observed adverse effects. BAK may be damaging to the ceils on tbe ocular surface, and, therefore, the amount to tbe formulation may be varied fo achieve an optimal level of ocular penetration of Compound-i, without compromising the ocular cel! layer integrity and increased toxiclfy.

[0122] irt some embodiments, the suspension optionally comprises buffers. Buffers when used, for example, can be sodium monophosphate basic, phosphoric acid andTris buffer. Compound-! concentration in suspension Is about 0.005% - about 5.0% w/v Tbe suspension prepared without additional buffer further composes about 0.005% BAK and about 2% glycerin and with a pH 6.O. in another embodiment the suspension prepared without additional bufier comprises about 13s pofysorbate 80. about C.i% tyioxapoi, about 0.2% Potoxamer 407, about 0.005% ΒΛΚ. about 2 0% glycerin, and with a pH 6.0.

[0123] in suspensions prepared in phosphoric acid/Tns, the suspension comprises about Q.1475 phosphoric acid, about 0 2% Tris base, about 1 0% polyserbaie 80, about 0.005% BAK, about 2 0% glycerin and with a pH 6 0 in one smbodirrterit, tbe suspension further comprises about 0.2% tyioxapoi Tbe pH of tbe suspension varies between about pH 8,0 and 7.2.

[0124] Tiie suspensions prepared in tromethamine [Tns) atone comprise about 1% polysorbate 80. about 0.107- ty-Iox3poi, about Q.2% Potoxamer 407. about 0.6% Tris, about 0.0Q5% BAK, and about 2.0% glycerin with pH 6.0. in another embodiment, a suspension prepared in Tns comprises, about 1 % Tns, about Q.45% NaCi, about 0.025% ΡΟΤΑ, about 0.2% BPMC. about 0.1%, polysorbaie 60. aboui 0.0051% BAK, with a pH 6.0. In ihese suspensions 1 N HCI end/or IN NaOH are used tor titration to appropriate pH.

[0125] Tbe suspension of the invention comprises about 0,005%, about 0.05%. about 0.1 %, about 0.2%, about 0.3%, about 0.4%. about 0,5%, about 0.6%. about 0,77% about 0,8%, about 0.9%, about 1.0%. about 2.079. about 3.0’%, about 4.0%, or about 5.0% of an active agent of Formulae (!). (Ii), or a pharmaceutically acceptable salt thereof, for example, Compound-1, and aboui O.O1% - about 0.05%. about 0.05 - about 0.09%, or about 0 09 - about 0.2% w/v sodium phosphate monobasic monohydrate and/or about 0.3% - about 1.O75 of Tris. In a specific embodiment, tbs suspension comprises about 0,14% or about 0.2% w/v Tns-buffer. in additional embodiments, suspensions rare prepared in about 0.675 Ths <x about 1.076 Tris Other equivalent buffer systems weil known in the art are also used in the suspensions of the current invention. In one embodiment, the Formula 11 compound or Compound-i is formulated as about 0.4% active agent, about 574 Cremophor RH4Q, about 2.0% glycerin, and about 0.005% BAK.

[0126] in some embodiments, the suspension of the invention has a pH value of about 4 0 to 7.5 si or under about 40' C [0127] Fqr exprftpie, ttie suspension of the invention has a pH value of about 6 0 at or under aboui 40 C.

[0128] in some embodiments, the suspension of ihe invention has a pH value of about 5.0 fo about 7.0 al or under

about 40 "C

Concentration in Various Qatiiar TisstJasOelivcreti as an Ophthalmia Suspe/ision [0129] in some embodiments. suspension of Compound-1 or its free base provides similar concentration of the active agent at the centra! choroid and the centra! retina compared to the concentration of the active agent dativered in Ge! Drop form {discussed inlm).

[0130] !rt some embodiments, Tns-bssed suspension of Compound-! or its free base increases fhe bioavaifability of the active agent at the centra! choroid and ihe centra! retina, white reducing concentration al ihe cornea. In some embodiments, topical delivery of Comjx?und-f or its free base formulated In Tris-base reduces corneal concentration by about 5-10x, 10-23/, 20-30X. 30-40x. or about 50-IOOx compared to ihe corneal concentration oi equimolar Compound-! or its free base delivered as a Gel Drop.

[0131] The combined effects of decreasing corneal drug exposure so as to avoid poor ocular toierabiiity while maintaining or increasing posterior segment bioavailability so as to increase inhibition of receptor tyrosine kinase (RTK). for example, VEGF, significantly increases the therapeutic index and corresponding benefits to patients.

[0132] Once or twice dally administration o' abouf 0 006% - about 5.0% w/v Compound-! suspension of the current invention for 30-93 days or 4 - S months is wel! tolerated in the eye.

Gei Drop (hot in accordance with the present invention) [0133] The ophthalmic composition or formulation may be formulated as a Gel Drop. The Gel Drop formutation includes no more than about 0.05% of sodium phosphate monobasic monohydrste to provide the required buffering capacity and free-flowing, filterable formulations at about 0 035% - abouf 2.0% Compound-! without Ihe need for surfactant additives. [0134] The Gel Drop formufation comprises aboui 0.005% Io about 2.0% w/v oi the active agent of Formulae (fj. (Ii), or a pharmaceuticaffy acceptable S3ft thereof, for exampte, Compound-!. The concentration of Compound-I or its free base (formula Si) in ihe Gel Drops may be about 3.005% - aboui 0,01%. about 0.01% - aboui 0.05%, about 0.05% -about 0.1%. about 0 1% - about 0 27« about 0.2% - about 0.3%, about 0.3% - aboui 0.4%, about 0.4% - about 9.5%, about 0.5% -· about 0.6%,. about 0.6% - about 0.7%,. about 0.7% - about 0.87(., about 0.8% - about 0.377, about 0 9% -about 1.0%, or about 1 0% - about 2.0% w/v for topical administration. The Gei Drops may include abouf 0.005% about (005%, about 0.1%. about 0,2%. about 0.3%, about 0.4%. about 0.5%, aboui G.6%, about 0.7%, about 0,8%, about 0.37η, abouf 1 C;%. or about 27> w/v of Compound-! or its free base (formula Ii) [0135] The Gel Drop ophthalmic composition may include glycerin as a ton icity agent. In some examples the ophthalmic composition includes mannitol. The glycerin or mannitol content star, amount to prevent any changes in the solubility of Compound-! and at a level of about 2 9 - about 2.530, glycerin provides an osmolality o! about 225 about 300 mOsm/kg depending on the phosphate concentration. Glycerin may be about 27» and phosphate may be about G.05% of the gel drop ophthalmic composition. The concentrations of glycerin and phosphate io in an amount that the tonicity level of the ophthalmic composition is about 240 mOsm/kg.

[0136] The Ge! Drop ophthalmic composition includes Benzalkonium Chtonde (BAK). in- some examples, the 8AK content is about 0.0057ο, sufficient for preservation of ihe ophthalmic composition agains! microblaf contamination in some examples, BAK is not required for use oi ophthalmic composition fo a sterile, single-use product.

[0137] The Gel Drop ophthalmic formulation of Compound-f inciudes; about 0.0057« - about 2.9%. Compound-I or its free base, abouf 6.05% sodium phosphate, about 27« glycerin as the tonicity adjusting ageni, aboui 0.0057« BAK as a preservative, water (purified, i e. distilled, or deionized! as a vehicle, and sodium hydroxide to adjust pH to 6.0. in one embodiment, no other excipients are added.

[0138] The Gei Drop comprises about 0.9057«·· about 2,07« of the active agent oi Formulae {!}. (II}. ora pharmaceutically acceptable saft thereof, for example. Compound-I, and about 0.01% - abouf O 05%. about 0.05 - about 0.09%. or about 0.0S - about 0.2% w/v sodium phosphate monobasic monohydrate. in one exampte. the Gei Drop comprises about 0.05%, about 0.27% or about 0.27« w/v sodium phosphate monobasic monohydrate buffer. Other equivalent buffer systems well known in the art are afso used in the Gel Drop Compound-! or its free base may be formulated as about 0.4% - abouf 2.0% active agent, about 5% Cremophor RH40. about 2.07» glycerin, and about ø 005% SAK.

[0139] The Gal Drop of Compound-I may include aboui 0.3% - about 2.0% (3-20 rng/mLj Compound-!, aboui 0.05% - about 0.2% Sodium Phosphate, and about 2% glycerin. The pH of the composition is between pH 5.0 - 7.9.

[0140] The present disclosure provides 6ei Drop formulated in the presence of excipients such as, without being iimiting exampte, Povidone, polysorbate 80 (PS801. polyethylene gfycoi (PEG] 400. tyioxapol. poioxamer, glycerin, and BAK in a phosphate buffer. £ye Drops [0141] Disclosed herein is a formufation, comprising the disclosed compounds as aya drops, a form of drug delivery that is pharmaceuticaiiy-acceptabie to patients, convenient, safe, with an onset of action of several minutes. A standard eye drop used in therapy according io U.S. federal regulatory practice is s-ente. have a pH of about 6.0-7.4. and, if to be used more than once, contains a preservative but has a limited shelf life after opening, usually one month, it the eye drops are packaged in a sterile. single use only unit-dose dispenser, the preservative can tie omitted [0142] One method of eye drop formutation comprises ihe purest form of ihe disclosed compound (e.g., greater than 99% purity), arid mix the compound with buffer and tonicity adjusters. io adjust for physioiogicat pH and osmofarity. Examples of buffering agents to maintain or adjust pH inctude, but are not limited to, acetate buffers, citrate buffers, phosphate buffers and borate Puffers. Examples of tonicity adjustors are sodium chloride, mannlto! and glycerin, in some embodiments, other pharmaceutically acceptable ingredients are also added.

[0143] The formulated solution is then aliquoted into either s plurality of discrete, sterile disposable cartridges each of which is suitable for unit dosing, or a single cartridge for unit dosing. Such a single disposable cartridge is, for example, a conical or cylmcricsi specific volume dispenser, with a container having side-watts squeezable m a radial direction to a longitudinal axis in order io dispense the container contents therefrom at one end c;l the container.

[0144] The present disclosure provides ophthalmic eye-drop suspensions packaged in muiti-dose form or sing!® dose form, for example, as a plastic bottie with an eye-dropper in multi-dose form formuiations, preservatives are required to prevent microbial contamination after opening of the container. Suitable preservatives include, but are nol limited to. benzalkonium chloride, thirneroast, chlorobutanot. rneihy! paraben. propyl paraben. phenyietfiyi alcohol, edetate diso-dium, sorbic acid, polyquatemium- i, or other agents known to those skilled in ihe art, and all oi which are contemplated for use in the present invention. Such preservatives are typically employed at a level of from 0.001 to about 1,0% wetghf/voiume.

[0145] Without wishing io be bound by theory, the formulation of the current invention in an eye drop provides a puise entry of the drug The route by which Compound-! obtains access to the posterior segment is not by direct diffusion through ihe cornea with subsequent diffusion through the aqueous humor, vitreous humor, retina and ultimately the choroid. Rather, the Coropound-f compound achieves noiabfe hioavaiiability posteriorly following topicai instillation using a circumferential route around, rather than through, the globe.

[0146] lb certain clinical conditions, the eye drop suspensions can be formulated with other pharmaceutical agents, m order to attenuate the irntanoy of the other ingredient and to facilitate clinical response. Such agents include, but are not limited to. a vasoconstrictor such as phenylephrine, oxymetazoflne. napihnzoiine or tetrahydrozotine: a roast-ceii stabilizer such as oiopatadine; an antihistamine such ss azeiastine: sn antibiotic such as tetracycline; a steroidal antiinflammatory drug such as betamethasone: a non-steroidal anti-inflammatory drug such as diclofenac; an imrnuncmod-ulator such as imiqutmod or interferons, and antiviral agents such as V3tacicfovir. cidofovir and trifluhdine, The doses used for the above described purposes vary, but are in an effective amount to suppress discomfort, itch, irritation. or pein In the eye When the compositions are dosed topically, the "pharmaceutically effective amount" of compound can generally be in a concentration range of from 0.05 mg/ml to about 10 mg/ml. with 1 to 4 drops administered as a unit dose 1 io 4 times per day. The rnosi common method of ocular drug delivery is the instiiiation of drops into the cornea i/,e., “eye drops") [0147] A key requirement is that the formulation bé stedte and produced in a sterile environment An ideal disciosed compound for use in ophthalmic suspensions should be soluble and/or miscible in aqueous media at normat ocular pH and tonicity. Moreover, the disciosed compounds should be stabfe, non-toxic, long acting, and sufficiently poient to counteract dilution of drug concentration by blinking and tearing.

Dosage Forms [0143] The formulation of the current invention may be suitable for ophthalmic use. The solution as described herein may be a clear, colorless, stente, isotonic, buffered aqueous free-flowing liquid preparation. The drug product has a pH of approximately 6.0 and may be stored at +5 *C. The drug product may be provided in a container closure system consistinp of a semi-iransoarent ophthalmic dispenser bottle with a dropper tip and csd.

[0149] in sdme embodiments, the clinical concentration of Compound-l ophthalmic suspension is 1,0 - about 2.0 mg/ml, about 2,0 - about 3.0 mg/ml. about 3,0 - about 4,0 mg/ml, about 4.0 - about 5.0 mg/ml, about 5.0 - about 6.0 mg/ml. about 5.0 about 10 0 mg/ml, about 10 - 26 mg/ml.

[0150] The strength of the compound is 0.1% 2.0% (1 mg/ml - 20 rog/rol). A desired pharmacologic activity {or concentration) of the formulation of the current invention against pathologic choroidal and retina! neovascuforization is achieved following ocuiar administration of formulations containing 0.1 to. about 0.2%, about 0.3%, aisout 0.4%. about 0.5%, about 0 6%. about 0 7%. about 0.8%, about 0.934. shout 1.0%, or 2.β% w/v of Compound-l. The current invention provides that, following topical ocular administration with an optimal dose (for example, between 0.1% and 2.0%) the phamrøcoiogi Gaily active concentration is achieved and maintained in the central choroid target tissue, in one embodiment the active agent {Formula ii or Cornpound-I) is formuiated as 0 1- 2.0% w/v concentration and is dosed once or twice a day per eye ier more than 60 consecutive days. The plasma concentrations observed following fopical administration are substantially below ttie level expected to produce systemic foxicity.

Tabie 2: In vitro Summary oi pharmacodynamic properties for Compound·!

[0151] In some smbod iments, Compound-i exbi bits potent inhibition of tyrosine kinase activr iy for several proang iogenie growth factor receptors, with fC58 of less than about iOOnM (see Table 3}. Compound-! also blocks tbe high-stfinity VEGF receplors. s.g.. VEGFR-VFIl-1. but with lower potency (with iCjy, of about122nM (60.41 rrg/rni.))

Tabie 3; In Vitro inhibition of Tyrosine Kinases using a 10-point Titration Curve (257nM -SØØØnM) for Compound-1

[0152] Although VEGFR inhibition appears to be essental for reducing vascuiar penneabiilfy and preventing further neovasouiar growth, the simultaneous inhibition ofVEGF signaling with inhibition or other growth factor signaling pathways ie.g.. PDGF and angiopoi8tins/T!e2) may be linked to unique therapeutic outcomes. The therapeutic outcomes of a broader inhibition of signaling pathways; may contribute to Ihe regression of newly established pathologic vessels rn the posterior segment of the eye.

[0153] in some embodiments, aboui SOØrrM (aboui 176.67 ng/ml.) ol Compound-! inhibits VEGFR-2 kinase function {see Tabte 4). Suostantéai blockade of a sirniiar set oi proangiogenic growth facior receptors, incfuding FGFRst-3. Tie-2. and EpnS-4 are also observed. An unexpected finding is that about 300 nM concentration; of Compound··! inhibits the VEGFR-2 kinase function, which fails within the typical range found in the centra! choroid arid retina following five days of topical ocular delivery.

Table 4; to Vitro Inhiijition of i yrosine Kinases bv 300nM(170 87 np/niL) Compound-I

Table 5; to vitro Inhibition of Tyrosine Kinases by 1 μΜ {568.3 ng/mti Compound-!

(coniinued)

Overview of Drug Substance and Drug Product [0154) Drug Product, Compound-! Ophthalmic formuiations for clinicat studies are manufactured in dosage strengths between 0 05% -1.0% (as Compound-)), in some embodiments. Compound-! dosage in the formulation is β 05%, 0.1 %, 0.2%, 0.3%. 0.4%, 0.S%, 0.8%, or 1.03% Compound-i Ophthalmic Formuiations {solutions or suspensions) are for daisy, single use, topical administration to the eye in a ciinica! setting in addition to the active ingredient, in some embodiments ihe drug product contains about β.005% BAK as a preservative, purified water as vehicle, and is pK-adjusted with sodium hydroxide- io pH 6.0.

Sodium Phosphate-based Gel Drop (not in accordance with the present invention) [0155] The ophthalmic benefits of Compound-i in a sodium phosphate-based formutation (listed in Tabie 6) results from the self-getting properties of the APt in buffers, such as sodium phosphate. Spontaneous formation of seif-forming, thixotropic gel of Compound-! trom a clear solution is formed by increasing active agent concentration in sodium phosphate. Once the active agent concentration in the phosphate buffer reaches super-saturated .state, insoluble particulates of Compound-! are observed within ihe get.

[0156] The current state of the art predicts that application of a get with increased viscosity to the surface of the eye would increase cornea! residence time, increased corneal residence time in turn facilitates ocular drug absorption. As a result, ihe intraocular drug concentrations of viscous gels would be increased in comparison to non-viscous forniuisriions, such as water-tike solutions. One way to increase viscosity is to use various viscosity-enhancing excipients, e.g., carboxy met by iceiiuicse, which in effect achieves increased intraocular absorption of different drug substances fotfowing topical ocular administration The present disclosure provides a ttiixoi ropic ye! of Compound--! formed in the absence of any viscosity-enhancing excipients. For example, when Compound-! is dissolved into a simple buffer, such as sodium phosphate, a thixoiropic gel :& formed. The thixotropic gel, which is formed without any viscosity-enhancing excipients, is formulated as a Gei Drop.

[0157] The present disclosure provides dose-depehdenf and ddsefftetiuency dependent delivery of Cdtripound-i to the posterior segment eye tissues.

[0158] The Get Drop formulations of ihe present disclosure {listed in Table 6) differ among each other m several aspects, such as active concentration, sodium phosphate concentration, presence or absence of tonicity (giycerin) or preservative (henzalkonrumchteride/BAK) agonis, solubilizing surfactants (polysorbafe 80, fyioxapol, and/or poloxamer). and pH

Tromethamine-hased Suspension [0159] The present disclosure provides a suspension of Compound-f in a tromethamine-based formulation. In some embodiments, the suspension of Compound-! in a tromethamine-based formufetion has equal to or mom then S5%. of the active drug substance in an insoluble form Tins characteristic is distinguishable from the soluble or semi-soluble

state of Compound-i m the Ge! Drop {the Gei Drop (gei), which is not an entirety soluble state as concentration of the active agent increases) or in .a Cyciodextrin-based formutation. Tromethamine-based formulations of Compound-i show increased futhidity with increasing active agent concentration Administering a topicai drop of Compound-f suspension to the eye, which is a combination of sc-iubie and Insoluble active agent components, are beneficial with respect to both safety/toierahility end efficacy.

[0160] The present disclosure provides Compound-f in the trorrethamine-based suspension, delivered at concentrations to Ihe target tissues between 10-lOOOx of the cellular ICS,-, for fhe various pro-angiogenic RTKs. See, e.g., Tabie 7. [0161] The comeai safety and toierabiiity of topical Compound-ι is a direct consequence of ihe amount of soluble (as opposed to insoluble) active agent applied to the cornea! surface, and the resultant comeai fissue concentration. In some embodiments, subjects who receive topical ocular administration of she tromethamine-based suspension are able to toierafe up fo higher level o; the active agent concentration in -he formulation, as compared to equimolar formulations of the sodium phosphate-based Gei Drop.

[0162] The present disclosure provides ocular bios vai lability of Compound-! in the posterior segment upon administration of a tromethamine-lxssed suspension The ocular bioavaftability of Compound-! In tbs posterior segroen; is directly proportional to the tola! amount of drug administered (insoluble pins soluble see Tabte 7). Although fhe insoluble drug particulates irre nol readily available to anterior segment tissues: the inherent and unique physicochemical properties of Compound-! allow both insoluble and soluble components to gam entry to posterior segment tissues, such ess fhte choroid and retina. Consequently, even higher drug concentrations than those achieved with Gei Drop formulations containing equivalent amounts of the active agent are achieved with shir tromethamine-based suspension Thus;, Irorneth-amine-based suspension provide, a; improved cornea! tolerability and bi increased btoavaiiabiitty to the posterior segment. particularly to the choroid, the primary target tissue ‘or treating neovascular (wet) AMD.

Cyctodextrin~based saiution (not in accordance with the present invention) [0163] Cyefodextrins. which are cyclic oligosaccharides made up of six fc eight dextrose units {«-. [I-, and γ-CDs) joined through one to four bonds, are well-known for their ability to act as a solubilizing agent for retativeiy insoluble drugs. See Stella & He. Cyclodextnns, Toxicol. Pathol., 36: 30-42 (2008).

[0164] 2-hydraxypropyt-jt-cyckKtexlrin (HP-iTOD, also known as KIEPTOSE® HPB) ai equal to. or more than 1:6 molar fistic or Sultobuiyieihcv-ri-Gyclodexirin (SBE-p-CD, aiso known :as CAPTtSOL·®! at β equal to or more than 1:2 ratio in the proposed clinical formulation. Compound-) or its free base Ophthalmic Solution, may provide sotebifity that meets clinical dose strengths of 0,1-1,0% Compound-!.

[0165] Cyciodextrin-imsed solutions of Compound-f or its free base tray no- only have improved solubility of ihe active agent into a uniform soluhon. hut, upon topical ocuiar administration, aiso have a novel and previously unobserved characteristic of significantly increased therapeutic index of the active agent at the posterior segment of the eye, The solutions of Compound-i of ihe prose nt disclosure reduce a rtfenor segment exposure, thereby increase the concentration of the active iri the solution and incterase frequency of its delivery m order Io maintain high posterior segment concentrations. Both of these beneficial characteristics Eire related to the known property oi cycfodextrin to form hydrophilic complexes wiih hydrophobic drugs. See Stella & He, Cyclodextrins, Toxicol. Pathol., 36; 30-42 (2008). When formulated with Compound-i or its free terse. cyciodextrin formed a clear, colorless solution which exhibited water-tike viscosity Following topical ocuter administration. Coropoond-l/cyciodex-nn complex has the appearance of being pharmacologically inactive and roetaboiicaffy inert. The Compound-i/cyclodextrin complex confers cornea! toierabiiity until cycfodextrin spontaneously dissociates from the active agent, thus making available high concentration of Compound-i at its intended site of action in the posterior segment of ihe eye, e.g., choroid and retina [0166] in some examples, cyeicdextrin-based solutions of Compound-! lower corneal exposures of Compound-i compared to Get Drop formufations at similar drug concentrations. The use of cyciodextnn-based soiutions of Compound-! provides about 10x reduction m corneal concentrations, as compared to dosmg with equimefer formulations oi the Gel Drop. In some examples, after 20 - 3C days of topical ocuter dosing of about 0.2 - 2 0%. e.g.. abouf 0 6%, Compound-f us a cyciodextrin based solution, no untoward findings are Eittrifcuted to test article or vehicle The present disctosure provides higher concentrations of Compound-! within the posterior segment target tissues, such as at the central choroid and Ihe central retina, when cyctodexirin-based solution of Compound-! is topically applied. In some examples, the combined effeds of decreasing comeai drug exposure s;o ess to avoid poor ocular ioierabiiiiy, white increasing posterior segment bioavailability so as to increase RTK inhibition, significantly increases the therapeutic index and corresponding benefits) to treated subjects, [0167] The present disclosure provides expansion of therapeutic window for both suspension-based formulations (see Example 3) and ihe cyciodextrin formufations due io significantly reduced exposure (about 10-100X or 1-2 fog reduction). The reduced exposure improves corneal ssifety/ioterablltty, which allows higher concentrations or frequency of dosing of Compound-! to be administered topically Tiw higher concentration enables Compound-i to achieve higher back of the eye target tissue concentration, which Improves the therapeutic efficacy of Compound-!.

[0166] Topicai ocular dosing of ophthalmic gel drops may be associated with high corneal tissue exposure (> ICOuMj and corresponding untoward observations in the anterior segment, such as discomfort, comeai and conjunctival inflammation, cornea; epithelial erosion and/or thinning and degeneration, in contrast, repeated topicai ocular dosing of Compound-;! ophthalmic solution produces comeai exposure that are roughly 5· to 10-fold fewer than an equimolar dose of ophthalmic gef drops, and are free* of untoward clinical or histopathologic findings. Topical ocular dosing with Compound-1 ophthalmic solution aiso achieves equal or higher target therapeutic exposure In the centra! choroid in comparison to an equimolar dose of the ophthalmic gel drop Oversill, the corobinafion of decreased comeai exposure and corresponding improved ocuter toterabifity. while simultaneously maintaining or promoting drug delivery to the posterior segment target tissues, along with improved physicochemical stability, provides greater benefit to subjects compared to the ophthalmic Ge! Drop formutation. ί- ίο 5-day PK results with topical ocular Compound-i in Cyciodextrin-based Solutions (not in accordance with the present in vent ion) [0165] Tbs present disclosure provides ocular pharmacokinetics of various formulations and dose regimens of Compound- i folio wing topical neo I or dose administration. Three dosage strengths in nine iS) different topical ocular formulations of Compound-I ana used for dosing rsitber once per day (q.d.) or twice per day {bid.) for 1,2,3,4. or 5 consecutive days. Subjects each receive about 30 pi. bilateral topical ocular dose of ore of three (3) Compound·! formulations, or vehicle formulation, using a positive displacement pipette, [0170] The composition oi each Compound-i formuiaiion is described in Table 8A. Aii doses were administered within 1 hour of the scheduled dose time On day 1, Groups , 2, 4-6, 8, 10, ί 1, 13. 15, and 17 receive one dose (q d 1 for either one ¢1) or four [4) days. On days 1 through 4, Groups 3, 7,9,12,14, and 16 receive p.l.d. dosing approximately 8 hours apart at 7:Q0 AM and 3:00 PM for four (4} days. Some subjects receive b.i.d dosing of vehicle only formulations for five [5i consecutive days.

[0171] In some examples, ocular sampling is performed at aoout 0,3. about 1, about 2, about 3. about 4. about 5, about 6, about 7, about 8. about 9. about 10. about f 1. about 12. about 13, about 14, about 15, about 16, about 17, about 13, ebout 19, about 20, about 21. aboui 22, about 23, or about 24 hours post-dose relative to the day 1 dose. Aqueous humor, cornea, centra! and peripheral retina, and centra! and peripheral choroid samples are coffecied io monitor effects of treatment. Aqueous humor, cornea, central retina, and central choroid samples am assayed.

[0172] Tabte 8A-C tisis 1- to 5-day PK results with topical ocular Compound-! in Cyciodextrin-based solutions.

Table 8A: Oouiar Formulations-

[0173] Tabie SB {isis average Compound-! concentrations in aqueous humor retina, choroid, and cornea (LLOQ: Lower L irnitof Quantitation, the L LQQ is the lowest enafyie concern rati on ihat ran be quantified with accepintite precision and accuracy,;

Tabie 8B

(cortSnusdj

[0174] Tabte 8C fists the summary of average ocular tissue concentrations of Compound-l in aqueous humor, central and peripherai retina, central and peripheral choroid, and cornea for Groups 1 through 10. Any vaiues <ILOQ were excfuded trom statistical calculations. When all values are <LLOQ for a given time point, <i.L.OQ are reported ss the average.

Tabte SC

(continued)

5-day PK results with topicai ocular Compound-! in Cyciodextrin-based Solutions (not in accordance with the present invention) [0175] The present discfosure provides ocuiar pharmacokinetics of various dose regimens of topicai ocular solutions of Compound-i containing hydroxypropyi-ii-cyc!od8Xtrini"HOj)CD'’)foi!owing ocuiar dose administration. Different topicai ocuiar solutions of Compound-! are administered either once per day (G,d.) or twice per day (b.i.d.) for either 4 or 5 consec utive days. Subjects each receive a 30 u.L bilateral topics! ocular dose of one of four Compound··! dosage strengths. [0176] All doses wen? administered with .t 1 hour of the scheduled dose time, except some subjects receiving on day 1. Ocular sampling after administration oi Compound-i Is performed one hour following ihe first daily dose on day 5 for subjects, except in a few. where ocuiar sampling is performed 24 hours after the first daily dose on day 4.

[0177] Aqueous humor, cornea, central and peripheral retina, and central and peripheral choroid samples are coliecied. Cornea, centre! retina, and central choroid samples are assayed; aqueous humor, peripheral retina, and peripheral choroid samples are not assayed.

[0178] Tabie 9 iA-E3? lists 5-day PK results with topicai ocuiar Compound-! in cyciodextrin-based solutions.

Tabie 9A; Ocular Formulaiions

(cortSnusdj

(continued)

[0179] Tabie 98 Sista a summary oi average ocular tissue concentrations of Compound-' in central retina, central choroid, and cornea. Any values <LLOQ were exciuded from statistical catenations. When aii values were <LLOQ for s given time point, <LIOQ was reported as the average.

Tabte 98: Average Compound-l concentrations in retina, choroid, and cornea.

Concentrations of Compound-i (in pM) in Various Ocular Fluids and Tissues [01 SO] in some embodiments. concentration of the active agent in various tissues and fluids of the eye is measured upon iopicaf ocutar administration o! a solution of about 0.4% (about 4 mg/ml.) Compound-i anti cyctodextnn. Average concentration of Compound-! Is measured in the centra! choroid, central retina, aqueous humor, and cornea. Compound-t is in a solution (0.4% or 4 mg/ml) with 3.41% KLEPTOSE® and 0,142% phosphate buffer; 8 3% KLEPTOSE® HPB and 0 14 2% phosphate: 4.88% CAPTtSOL® and 0 142% phosphate; or 4.88% CAPTISOL® ano 0,122% phosphate. See Table 50A-B, [0181] in some embodiments, upon topicai ocutar administration of a sotuiion of about 0.4% (about 4 mg/mt) Compound-! and cyciodexinn. the centra! choroid concentration of Compound-! is between about 0.2 μΜ and about 0.8 μΜ, The centra! retine concentration of Compound-! is between about 0.05 μΜ - about 0.15 μ.Μ. in some embodiments, upon topicai ocular administration of a solution of about 0.4% (about 4 mg/mLj Compound-! and cyctodextnn. the aqueous humor concentration of Gompound-I is between about 0 003 μΜ - about 0.008 μΜ. And the cornea! concentration fit Compound-! is about 8.0 y.M - about 40 μΜ. KIEPTOSE® HPB or CAPTISOL·© is used in the solution of Compound-t administered topically to the eye.

[0182] in some embodiments, mean Compound-! ocuiar tissue concontrstions following twice daily topicai dosing with 0.31% Compound-! ophthalmic go! drop formulations with and without benzylaikcrnturo chloride is highest m the cornea With between aboui 200 j;M - aboui 350 (iM in the corner!, between about 2 h (tM - about 5.0 in the peripheral choroid, between about 0.2 μΜ - about 0.7 μΜ in the centra! choroid, between about QQ5 μΜ - about 0.5 p.M in the peripheral rehna, end between about 0 01 μΜ - about 0.05 μΜ in the aqueous humor.

[0183] in scree embodiments. Tris-basixt suspension formulations ci Compound-i is well tolerated, without any corneal findings.and only with a few sporadic incidences of miid conjunctivitis. in sortie embodiments. mean Compound-1 ocuiar tissue concentrations, assessed at 1 hour ·>· 15 minutes after the first daily topical ocular dose on day 30 for the twice deity topical dosing with 0.3% Compound ! Tns-based suspensions with and without benzylaikomum chloride, are highest in the cornea, for example, between about 2 00 μΜ - about 4 ΟμΜ The peripherat choroid concentration from ihe same dose is between about 0.7 μΜ - about 1.5 pM; the central choroid concentration is between about 0.3 f>M - about 0.4 μΜ; ths peripheral retina concentration is between about 0.08 μΜ - about O.OS μΜ); central retina concentration Is between about 0.04 μΜ - about 0.0? ·αΜ; and aqueous humor concentration is aboui 0,001 p.M - about 0.002 uM. [0184] The present disclosure provides Cyciodextrin-based solutions (e.g., solutions comprising hydroxypropyf-beta-cyciodexirin (HP-jt-CD, KLEPTOSE® HPB)) of Compound-i that were well toierated when administered topically tor up to 30 days, twice ciaiiy ai about 0.1% Compound-l (in a solution with aboui 20% - about 2.5% ΗΡ-β-CD). twice daily at about 0.2% Compound·-! {it! a solution with about 4.0% · about 4.5% HP-i'.-CO), once or twice daily at about 0.4% Compound-! (in a solution with about 8 0% - about 8.5% HP-p-CD), and once or twice daily at aboui 0.51½ Compound-i (in solution with up to about 14% ΗΡ-β-CD) in subjects. Moreover, in additional examples, cyciodextrin-based solutions of about 0 4% w/v Compound·! in KLEPTOSE® HPB, KLEPTOSE® HP. or CAPTISOL® are? wett-toierated when dosed twice daily for up to 24 days.

[0185] The present disclosure provides dose-limit ing comes! toxicity observed with Compound-! ophthalmic Ge! Drop formulations, in some examples, ophthalmic Gel Crop renders about five-fold to about fifleen-told higher corneal concentrations of Compound-i compared to cyciodextrin based solution, and aboui fifty-fold to about hundred-fold higher corneaf concentrations of Compound-! compared to Trie-based suspensions. Compound·! Tris-based suspensions and cyciodextrin-based solutions (if tiie present disclosure are well ioferated with no evidence oi overt ocular toxicity, tn some embodiments, once or twice daily administration for ai least 30 days of about 0.005% to about 5.0% w/v oi a cyciodextrin-based solution or a Tris-based suspension of Compound-! is well tolerated in suhiects. The present disclosure provides highest central choroid concentrations of Compound-l using Cyc.!odextn.n-based. solutions compared to equimoiar doses of the gels and/or Tris-based formulations.

Tabie 10A: Average concentration of Compound-! in μΜ in various ocuiar fluids and tissues

Tabie 1S8: Study Design

I0188J Tabie 11 shcwslhe cornea! and central cbørøiciaiconcentrations øf Compound«! femuiiations,

Table 11:

Phase I Froiocof for Dose-Escalation Study in Patients with Neovascular ΑΛ/ID

[0187] The present disclosure provides a Phase ! siudy involving a twelve-week, open-iabei, dose-escalating, multi-center t rial to evaluate the safety, tolerability, and pharmacokinetics following topical ocular administration of Compound-i in patients with neovasculsr age-related macular degeneration (AMO) Up to 60 patienls total are treated one io two tiroes daily with topical ocutar dosing of Compound-! ophthalmic solution for three months, where three dose-escalating monotherapy arms and one adjunct therapy arm using a single intravifreal injection of LUCENTiS® plus the maximally-tolerated roonciherapy doss; are planned {15 patients per treatment arm). Patients that meet pre-specified vision and CNV lesion criteria confirmed by an independent reading center are allowed· to simultaneous!y discontinue topicai ocutar

dosing and receive treatment with siandsrd-of-aare.

[01S8] Th(5 present disclosure provides 3 dosage strengths, ranging from 0.1% to t.0% (w/v) (as Compound-!; ophthalmic solution for ciinicai studies. The strengths are about 0.1%, about 0 3%. about 0.6%. and about 10-¾ (w/v) Compound-! HCI.

Formutation Preparation [0189] Nori-limitihg examples of formufations of the present discldsUfe are outiinéd tn Table 12,

Table 12: Overview of product compositions tested in product screening studies

Doses Of Tr-eairaerti [0190] The formulation of the current invention is effective in treating or preventing (re., regression) choroidal and retina! neovascularization (NV) in the eye of a mammalian subject The Compound-! of the current invention, at a specific dose, inhibits a receptor tyrosine kinase. In some embodiments, the Compound-i formulation, ai a specific dose, Inhibits receptor tyrosine kinase including. VEGFR, FGFRs Tie2. and EphB-4. The inhibition of several RTKs by the formulaiion of the current invention, at a specific dose, simultaneous and has a synergisiic effect, and ts effective in fhe treatment or regression of NV in the- posterior segment of the eye.

[0191] in further embodiment, the formutation oi the currant invention Is effective in treating NV when administered one. two, three, and four times daily by topicai ocular delivery of 0.1% - 2,0’% (5 mg/ml - 20 mg/mL) of Compound-!, The formulation oi Compound-i or its free baste (Formula II), for the treatment or regression oi NV, is a solution comprising cyciodextrin or »a a suspension comprising Tris. The solution or suspension when delivered to a subject exposed to atmospheric oxygen to induce oxygen induced retinopathy iOiP) or NV. for example, is able to effectively reduce the mean area of pre-retmaf NV per retina. The prevention or treatment of NV by Compound-l formulation and/or suspension is achieved via inhibition of several receptor tyrosine kinases (RTKs). including VEGFR·?:.

[0192] Any of the disclosed diseases or conditions described herein can be treated or prevented by achieving target tissue concentration of from about 200 nM - about 2 p.?vS of the disclosed compounds or pharmaceutically acceptable salts, formulation and/or suspension thereof. In one embodiment, the formulation of the invention is for use in the treatment of pathoiogio angiogenesis in the posterior segment of the eye, achieving target tissue concentration of about of about 200 nM - about 2 jt.M of the disefosed compounds or pharmaceutically acceptable salts, and/or formulation thereof. Another iteration of this embodiment relates to actiieving target tissue concentration of about 300 dM - shout 2 μ M of one or more of the disclosed cornpou nds or pharmaceutically acceptable salts, and/or formulaiion thereof.

[0193] Iri an embodiment of the current invention about 0,2 - about 1.0% (about 2 - about 10 mg/ml) of Compound-! formulated as a suspens ion, uponadministration, may effectively inhibit VEGFR-2 kinase function and provide substantia! blockade of a set of proanglogenic growth factor receptors, including FGFRst-3, Tie-2, and EphB-4. The .2 10 rog/mL concentration of the Compound-1 in the formulation provides effective pharmacologically effective concentrations of drug to the central choroid and retina following 1-5 days of topical ocuiar delivery, [0194] in some embodiments, ihe exposure time of Compouno-f is between 1 and 90 days In some embodiments, the dosaga regimen involves severs·! courses of topical ocuiar administration of a formulation comprising Compound-!

to 3 subject for between 1 end 90 days. For example, the dosage regimen involves once daily, twice daily, three times daify or four times daily administration of the formulation for between i and 90 days. For example, the dosage regimen involves once. twice, three times, or four times; administration of the formulation on every other day (i.e.. on day 1. 3. 5. 7 etc.) for up to 90 days. For exempts, the dosage regimen involves administering once on day f, once or twice on day 2 - day 90 For example, file dosage regimen involves administering once, twice. three times, or four times on day 1, followed by once daily for 2-90 days. For example, foe dosage regimen involves administering once, twice, three times, four times on day 1, followed hv once, twice, three times, or tour times ori every other day (i.e., on day '.3.5.7 etc.) for up to 90 days. For exam pie, one dosage regimen involves once per day or twice per day for 1.2, 3,4, or & consecutive days For iwice or three daily dosage regimen subjects receive topical ocular dose of a Compound·! formulation on days 1 and 4 approximately about 4. 6, or 3 hours apart. in another embodiment, subjects receive topical ocular doses of a Compound-l formulation approximately about 4,6, or δ hours apart for tour consecutive days, tn some embodiments, subjects receive one or two doses of topical ocutar dose of Compound-f formulation per day for 5 consecutive days, tn yet other embodiments, subjects receive one or iwo doses of topical ocular dose of Compound-! formulation for 5-90 consecutive days, in some embodiments, subjects receive one or two doses of topicai ocutar dose of Compound-! formulation for at least 2£ consecutive days. Sn one embodiment, subjects receive one or two topical ocuiar doses for at feast 90 consecutive days or more. (0195] In some embodiments, the presentdisctcsure provides a formutation of Compound-! or its free base administered topically to the anterior segment of the eye of the subject to treat AMD, pathologic CNV, and/or pathologic NV. For example, the formulation is administered io the eye of a subject i. 2, 3, or 4 times daily, in specific embodiments, the fcirnuiailon is administered io the eye of a subject 2 or 3 times caily. For example, the formulation is administered to one eye or both eyes of a subject For example, about 1 mg/mt of an active agent comprising formulalion of foe current disclosure is administered twice a day (13f D) to one eye or both eyes of a subject, in some embodiments, about 2 mg/mL BiD, about 3 mg/mt. once a day (QD) or BID, about 4 mg/ml. QD or BiO, about 5 mg/ml. QD or BID. or about 6 mg/ml, QD or BiD of is administered to one eye or both eyes of a subject.

[0196] For example, a formulation comprising about 2 rng/mL BID of Cornpound-ί is administered to one eye or both eyes of a subject for between '1 and SO days, in some embodiments a formuiaiion comprising about 3 rng/mL BID of Compound-t is administered to one eye or both eyes oi a subject for between 1 and 90 days, tn some embodiments a formulation comprising about 3 mg/ml QD of Compound-l is administered to one eye or bolt) eyes oi a subject for between ί and 90 days in some embodiments s formulation comprising about 4 mg/mt ΒΪΟ of Compound-i is administered Io one eye or both eyes of a subject for between 1 and 90 days, tn some embodiments a formulation comprising about 4 mg/mt QD el Compound-i is administered to one eye or both eyes of a subject for between 1 and 90 days in some embodiments a formulation comprising about 5 mg/ml 8ID of Compound-i is administered to one eye or both eyes or a subject for between t and 90 days, in some embodiments a formulation comprising about 5 mg/ml QD of Compound-i is administered io one eye αι both eyes oi a subject for between 1 and SO days, in some embodiments 3 formulation comprising about 6 mg/ml BID of Compound-t is administered Io one ays or both eyes of a subject for between 1 and 90 days. In soma embodiments »formulation comprising about 6 mg/ml QD of Compound-! is administered to one eye or both eyes of a subject for between ' and 90 days. The dosage regimen for between 1 and 90 days may be any of the regimens involving consecutive or alternate days described m the paragraph above.

[0197] The present disclosure provides iarmufatioris as shown in Table 13 for administering Io one eye or boih eyes of a subject.

Table 13

(continued)

[0198] in some embodiments, the form ulatton of Formula (II) or Compound-! is administered to one eye or both eyes of a subject For example, aboui 0.2 % - about 0.6% (w/v) of the compound of Formula (ii) or about G 1% - Q- 7 % (w/v) of Compound-ί comprising fonmuiation of the current disclosure is administered once a day (QD) or twice a day (BiD) io one eye or both eyes of a subject for between 1 end 90 days, tn some embodiments. Formula (ii) compound or Compound ! is comploxcd with a coroptoxlng agent, e.g.. cyciodextrin (e.g .. KLEPTOSE-s HPB (% t) m rot.o of aboui 1:3. in which about 2% -13 % (w/v) cyciodextrin (e.g., KLEPTOSE® KPB {%}) is added to ihe formulation. The formuiaiion further comprises aboutG. 1 % - about 0.2% buffer, e.g.. 10 mM phosphate buffer The desired osmolality of the foundation is about 2ϋΟ - about 300 mOsm, achieved by ridding tjuanuty sufficient to achieve the osmolality with a sail, e.g . sodium chloride. The pH of the formulation is about 6.0 at or under about 40 :,C. The dosage regimen for between 1 and 90 days may be any of the regimens involving consecutive or alternate days described in the paragraph above.

[0199] ι he methods of the present disclosure are combined with the standard of care, including but not limited to laser treatment and treatment with injectable anii-neovascuiar agerris. Formulations lor use in the treatment of diseases or conditions of trie eye [0200] Disclosed are formulations for use in the treatment of diseases or conditions of the eye. The disefosed formulations are used for treating, preventing, or controlling ocular neovascularization (NV). or treating a disease or condition that is related io the onset of N V by administering to a subject one or more of tbe disclosed compounds, and formulations ttie roof.

[0201] One aspect oi tiie disclosed use of the formulation relates to treating or preventing NV by administering to a subject an effective amount of one or more of the disclosed compounds or pharmaceuticaily acceptable sails, and/or formulations -hereof One embodiment of this aspect relates to a method for treating NV by administering to a subject a composition of·, a) an effective amount of one or more of -he disclosed compounds or pharmaceutically acceptable salts, andfor formulations thereof, and optionally b) one or more carriers or· compatibfe excipients [0202] The disclosed uses relate to preventing or controlling pathoiogic ocular neovascularization (NV), or treating a disease or condition that is related to the onset of NV by administering tc a subject one or more of the disclosed compounds, and formuiatiofts thereof, [0203] Tiie current embodiments provide a formuiaiion ol Compound-i or its free base (formula Ii} for use in a method of treating a subject with a posterior segment disease vasculopathic or inflammatory disease of the eye. These include for example, diabetic retinopathy (including background diabetic retinopathy, proliferative diabetic retinopathy and diabetic macular edema); age-refateci macular degeneration (AMD) (including neovascuiar (wet/exudative) AMD, dry AMD, anti Geographic Atrophy); pathoiogic ohonoidai neov3scuiariz3t:on (CNVj from any mechanism (i.e, high myopia, trauma, sickle ceff disease; ocuiar histoplasmosis, angioid streaks, traumatic choroidal rupture. drusen ol ttie optic nerve, and some retina! dystrophies)' pathologic retinal neovascularization from any mechanism {/.&., sickle cell retinopathy, Tales disease, ocuiar ischemic syndrome, carotid cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic occlusive artedoiitis; birdshot retinochoroidopathy, retinal vasculitis, sarcoidosis, or toxoplasmosis); uveitis; retina! vein occlusion (central or branch); ocuiar trauma; surgery induced edema; surgery induced neovascularization: cystoid macular edema; ocular ischemia; retinopathy of prematurity; Coat’s disease; sickle cel! retinopathy and/or neovasoutar gtauooma [0204] In one aspect c-f the current invention the formulation is for use in ihe treatment cf age-related maculat degeneration (AMD) (including neovascuiar (wet/exudative) AMD, dry AMD, and Geographic Atrophy). The solutions or suspensions may be for use in tiie treatment of neovascuiar (exudative or wet) AMD. In another embodiment, ttie solutions or suspensions are for use in treating dry AMD. in yet another embodiment, the solutions or suspensions are for use in treating Geographic Atrophy [02OS] The formulation of the current invention prevents, delays, or treats the onset of pathologic choroidal neovascularization (CNV) from any mechanism (i.e. high myopia, trauma, sickle ceif disease, ocular histoplasmosis, angioid streaks, traumatic choroidal rupture, drusen of the optic nerve, and some retinal dystrophies) in subjects [0206] The formulation cf the current invention delays onset, prevents progression, or treats formation of pathotogical choroidal -neovascularization (CNV) beiow the: neurosensory retina. The formulation of the cotTent invention is effective

in treating CNV

[0207] The formutation in one aspect is for use m the method of treating or preventing ocular neovascularization by administering io a subject an effective amount of one er more nf the disclosed compounds or pharmaceutically acceptable sails thereof. One embodiment of ibis aspect relates to s method for treating ocutar edema arid neovascularization by administering to a subject a composition of: at an effective amount of on« or more of the disciosed compounds or pharmaceutically acceptabte sails, and/or formuiations thereof, and cpiionalty b) one or more carriers or compatible excipients;.

[0208] The formutation in one aspect is also for use in the method of preventing or controlling ocular edema or treating a disease or condition that Is related to the onset of ocuiat edema by administering to a sutjjeci one or more or the disclosed compounds [0289] The formulation m one aspect is for use in the method of treating or preventing ocuiar edema by administering to a subject an effective amount of one or more of the disclosed compounds or pharmaceuitcally acceptable salts thereof One embodiment of this aspect relates to a method for treating ocutar edema by administering to a subject a composition of: a) an effective amount of one or more of the disclosed compounds or pharmaceutics tty acceptable sails and/or formulations thereof, and optionally b) one or more carriers or compatible excipients.

[0210] The formulation in one aspect is for use in the method of preventing or controlling retinal edema or retinal neovascularization or treating it disease or condition that is related to the onset of retinal edema or retinal neovascutar-ization by administering to a subject one or more or the disciosed compounds. One aspect of this method relates to treating or preventing retinal edema or retinal neovascularization by administering to a subject sn effective amount of one or more of She disciosed compounds or pharmaceutically acceptable salts thereof One embodiment of his aspect relates to a method for treating reiinal edema or retinal neovascularization by administering to a subject a composition of: a) an effective amount of one or more of the disclosed compounds or pharmaceutically acceptable salts, and/or formulations thereof, and optionally bj one or more carriers or compatible excipients.

[0211] Another embodiment of ibis aspect relates to a formulation for use in delaying or preventing progression of non-protiferative retinopathy to proliferative retinopathy by administering to a subject a composition of: a) an effective amount of one or more of the disciosed compounds or gliarmaceuficaity acceptable salts., and/or formulations thereof, and optionally bi one or more carriers or compatible excipients.

[0212] The formulation in one aspect is for use in the treatment of diseases that are a director indirect result of diabetes, inter aits, diabetic macuiar edema and diabetic, retinopathy The ocuiai vasculature of the diabetic becomes unstable over time tending to conditions such as non-protiferative retinopathy, macular edema, and proliferative retinopathy. As fturd leaks into the center of the macuta. Ihe part of the eye where sharp, straight-ahead vision occurs, the buildup of ffuid and the associated protein begin to deposit on or under the macula. This results in swelling that causes the subject's central vision to gradually become distorted Tins condition is referred to as "macular edema?' /Another condition that may occur is non-prcliferative retinopathy in which vascular changes, such as microaneurysms, outside ihe macuiar region of the eye may be observed During proliferative DR, pathologic new blood vessels grow in and up from the retina into to the vitreous body, where these abnorme! vessels may alter retinal morphology In the macula, and/or hemorrhage into the vitreous and obscure the visual axis.

[0213] The formulation in one aspect is further for use in the method of treating, preventing or controlling diabetic retinopathy or treating a disease or condition that Is related to the onset a!'diabetic retinopathy by administering to a subject one or more or the disciosed compounds.

[0214] The formulation In one aspect io for use in the method of treating or preventing diabetic retinopathy by administering to a subject an effective amount of one or more oi the disclosed compounds or pharmaceutically acceptable salts thereof. One embodiment of this aspect relates to a method for treating diabetic retinopathy by administering to a subject a composition of: a) an effective amount of one or more ot the disciosed compounds or pharmaceutically acceptable salts, and/or formula-tons thereof, and optionally b) one or more earners or compatibie excipients [0215] Diabetic proliferative retinopathy is characterized by neovascularization. The new blood vessels are fragile and are susceptible to bleeding. The result is scarring of the retina, as well as occlusion or total blockage of the light pathway through the eye due to the abnormal formation of new blood vessels. Typically subjects having diabetic macular edema are suffering from the non-proliferative stage of diabetic retinopathy; however, it is not uncommon for subjects to only begin manifesting macuiar edema at the onset of the proirferafive stage.

[0216] Vet further the formutation in one aspect is for use in the method of preventing or controiiing diabetic macular edema or treating a disease or condition that is related to the onset of diabetic macular edema by administering to a subject one or more or the disclosed compounds [0217] The formulation in one aspect is for use- in the method of treating or preventing diabetic macular edema by administering to a subject an effective amount of one or more of the disclosed compounds or pharmaceutically acceptable salts, or formulations thereof One embodiment of this aspect relates to a method for treating diabetic macular edema by administering to a subject a composition of: at art effective amount of one or more of the disciosed compounds or pharroaceutieatiy acceptable salts, and/or formulations thereof, and bl one or more carriers or compatible excipients.

Kits [0218] AKo disclosed are kits of the disclosed compounds and compositionsfor drug delivery into a human,„mammal or cell. The kits «tn comprise one or more packaged unit doses of a composition comprising one or more compounds to be delivered into a human, mammai. cr ceii. The unit dosage ampoules or multi-dose containers. in which the compounds io be deflvered are packaged prior io use, can comprise a hermeticaiiy sealed container enclosing an amount of the active agent or pharmaceutically acceptable sail, or formulation thereof, suitable for a pharmaceutically effective dose thereof, or multiples of an effective dose. The compounds can be packaged as a sterile formulation, and the hermeticaiiy sealed container is designed to preserve sterility of ihe formulation until use.

[0219] The kit of the current invention has a single-use eye drop dispenser bottle for delivery of ophthalmic formulation, in an alternative embodiment, the kit of the current invention has a multi-use eye-drop dispenser bottle. The rouiti-dose dispenser bottle has appropriate amount of anti-infeciive and/or preservative agent, for example without berng limited to. 0.005% BAK. The ophthalmic dispenser of the current invention has a top and a cap, The container of the current invention has a semi-transparent LORE ophthatrnic dispenser bottle wiih a LORE dropper tip and HOPE cap. The container may be of other type and form as needed and/or as used in the art.

[0220] The following examples are illustrative. but not limiting, of the meihods end compositions of the present invention

EXAMPLES

[0221] Compound-! is a potent and selective small molecule inhibitor of VEGFR-2. along with other proangiogenic RTKs such as the FGF receptors (F'GFR-1-3). Tie-2. and the ephhn receptor B4 (ERHB-4). Compound-i was shown to inhibit phosphorylation of specific RTKs, endofbeiiai cel! proliferation, and pathologic angiogenesis following systemic administration m murine cornea and rat growth plate models, as well as the growth of human tumor xenographs in athyrnic mice. Regarding potential ophthalmic indications. the Examples of the current invention described below demonstrated that topicai ocular delivery of Compound-! provided significant inhibition of pathologic retinal and choroidal neovascularization in clinicaliy-relevant rodent mode's. A summary of these data follows.

[0222] The following studies were conducted to measure ihe effect of the disclosed compounds on vascular leak and neovascularization of retina tissue, EXAMPLE 1

Primary Pharmacodynamics [0223] in Vitro Efficacy Pharmacology of Compound-i. Compound-1 potently inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor-2 (VEGF-2). as wel! as a select subser of other proangiogenic RTKs, during various in vitro assays Specifically. Compound-! compound blocked VEGF stimulated VEGFR 2 phosphory-ation in whole ceils along with the proliferation of cultured endothelial ceiie. Compound-i Inhibited recombinant tyrosine kinase activity of VEGFR-2 and FGFR-2 with a 50% inhibitory concentration (ICg.,,) c?f 10.55 nM {6 ng/ml) and 8.79nM (5 nc/mt.), respectively, and inhibited VEGFR-2 autophosphoryiation in intact ceils with an iC5J = 5 27 nW (3 ng/m!..j This inhibition was selective versus many other tyrosine kinases e.g., the VEGFR-2 tCyj was approximately 50Cx and iQOOx lower than those for epidermal growth factor receptor (EGFR) and the insulin receptor (IR) tyrosine kinases, respectively (see Table?) [0224] When using a 1O-point titration curve that ranged from 257 to SOC'Ori Μ ( i46 -2845 ng/mL), Compound-! exhibited potent inhibition of tyrosine kinase activity for several proangiogenic growth footer receptors, as evidenced by an !Cs;, < lOOnM (56.89 ng/mL.) -see Table 3). The iCS)JSi tor this select group of kinases were as follows: recombinant. KDR (human isoform of VEGFR-2) = 1.2?nM (0.72 ng/ml). Tie-2 = W.IOnM (5.75 ng,'ml), and FGFRs 1-3 = 8.50nM (4,84 ng/mt). 3.08nM (i .75 ng'mb, and 33.9nM (19,29 ng/ml), respectively. The compound also blocked the other high-affiniiy VEGF receptor. VEGFR-vFit-l, but with lower potency: !Csc, = 122nM (69,41 ng/ml}.

[0225] Although VEGFR inhibition appears to be essential for reducing vascular permeability and preventing further neovascular growth, the simultaneous inhibition of VEGF signaling with inhibition of other growth factor signaling pathways (e.g.. PDGF and angiopcietins/Tie2) may be finked to unique therapeutic outcomes. The therapeutic outcomes of a broader inhibition of signaling pathways may contribute to -he regression of newly established pathologic vessels in the posterior segment of the eye.

[0226] 300nM (170.67 ng/ml} of Compound-! completely inhibited VEGFR-2 kinase function {.see Tabie 4) and provided substantial blockade of a similar sei of proangioqenic growth factor receptors, including FGFRs-l-3, Tie-2, and EphB-4. An unexpected finding was that the 300 nfvf concentration was abte to completely inhibit the VEGFR-2 kinase function This concentration falls within the typical range found in the central choroid and retina following five days of topicai ocular delivery in mbbits and doge.

Overview of Drug Substance and Drug Product [0227] Drug Substance: The active pharmaceutical ingredient (APS), Portnois !! Hydrochloride (Cornphi ind-l CP-547,632-01), is a small molecule o' a single polymorph. The API substance is consistently manufactured tn purity exceeding 99 7% Any impurity in drug substance ;.· 0.15% is Suitably qualified >n toxicoiogy studies and the cunent specification for new unknown individual impurihes is sot to NMT 0.2% The fine! drug substance end drug product are analyzed. using standard methods.

[0228] Drug Product: GorhfJOund-i ophihalmic formulations for ctinicai studies was rnapufectured ih.dOsage-sffengibs between 0.05%-1 0% (as Compound-1) The strengths used lot theGLP batches are 0% (placebo), 0.05%. 0.1%. 0.2%, 0.3%, 0.4%, 0.6%. 0.8%. and t .0% Compound-!. Compound-i ophthaimio formulaiions (solutions or suspensions) ate used for daily, single use, topical administration to the eye in the clinical trial, in addition to the active ingredient, the drug product contains 0.005%, BAK as a preservative, purified water as vehicle, and is pH-adjusied With sodium hydroxide to pH 6.0, EXAMPLE 2

Sodium Phosphate-based Set Drop (not tn accordance with the present invention) [0229] The ophthalmic benefits of Compound-i in a sodium phosphate-based formuiaiion (listed in Table 8) results from Oie sett-getting properties of the API i n buffers, such as sodium phosphate. Spontaneous formation of a soil-forming, thixotropic gel oi Compound-! from a clear solution was formed fry increasing API concentraiion in sodium phosphate. This gel initially appeared clear and then demonstrated increased thickrsess/viseosity at higher AP! concentrations, as well as becoming increasingly more opaque, i.e , turbid. Once Ihe APt concentration in the phosphate buffer reached supersaturated state, insoluble particulates of Compound-1 also were observed within ihe gel.

[0239] Application o’l a go! with increased viscosity to the surface oftheeye increases corneal residence time, increased cornea! residence time in turn facilitates ocular drug absorption. As a result, the intraocular drug concentrations ol viscous gels increase in comparison to non-vtscous formulations, such as water-iike solutions One way io increase viscosity is to use various viscosity-enhancing excipients, e.g., carboxymethytceltufose, which in effect achieves increased Intraocular absorption of different drug substances foliowing topical ocuiar administration. In this study, however, a thixotropic get of Compound-! was unexpectedly formed in the absence of any viscosity-enhancing excipients. For example, when Compound-i was dissolved into a simple buffer, such as sodium phosphate, a fhixc-iroplc ge! was formed The thixotropic get, which was formed without any viscosity-enhancing excipients, was formulated as a Get Drop in this Example. [0231] The Get Drop of Compound-i was applied io eyes of Dutch-betted rabbits. Ge! Drops of Compound-! were administered to Dutch-Belied rabbits for 4 or 5 consecufive days, with three times daily dosing. The concentrations of Compound- f at the target tissues were measured at 1 hour following the last administered dose. Delivery of Compound-! tc the posferior segment tissues was dose dependent and dose frequency dependent.

[0232] The Ge! Drop formulations (listed in Tabie 6) differed in several aspects, such as AP! concentraiion, sodium phosphate concentration, presence or absence of tonicity {glycerin) or preservative (benzatkomumchionde/BAK) agents, solubilizing surfactants < polysorbate 80, tyioxapoi, and/or poloxamer), and pH

EXAMPLES

Tromethamtne-based Suspension [0233] Compound-l (about 1 mg/ml, to aboui 10 mg/ml.) in a tromethamine-based formulation formed a suspension. The suspension of Compound-l in a tromethamine-basso formulation had >35% of ihe active drug substance in an insoluble form. This characteristic is distinguishable from the soiubie or semi-soluble state of Compound-! In tne Gel Drop (ihe Gel Drop (gei) is not an entirely soiubie state as concentration of the active agent increases) or in a Cyciodextrin-based formulation. Tromethamine-based formulations of Cornpound-I showed increased turbidity with increasing active agent concentration. Administering a topicai drop of Compound-! suspension to the eye (which is a combination of sofuicleiancilnsoiubiéapBvoggénicbrfiponenfsjwasexpecisdfepreytdeuhiquebenefitsreievahitdboth&afety/toierabifiiy and efficacy, [0234] Tromethamine-based suspension of Compound-! was administered to Dutch-Belted rabbits for 4 or 5 consecutive days with three times daily dosing. Ocular tissue and piasma concentrations of Compound--! were measured at 1 hour following the Iasi administered dose. Compound-i in the tromethamine-based suspension delivered concentrations to the target tissues between W-IOOOx of its cellular 133:,-, for the various pro-angiogenic RTKs See 1 able 7, [0235] The corneal safety and -oierabiiity of topical Cornpound-I was a direct consequence of the amount oi soluble (as opposed to insoluble) active agent applied to the corneal surface, and the resultant comeai tissue concentration.

Animate that received topical ocular administration of the tromethamine-based suspension were able to tolerate up to higher level of the active agent concentration in the formulation, as compared to equimolar formulations of the sodium phosphate-based Gei Drop Results obtained from both Dutch-belted rahbiis and beagle clogs suggested that ocutar side sftects, such as discomfort and inflammation and in same cases, corneal thinning, wore more consistently observed when the comes concentration of Compound-l exceeded WGpM

[0236] Administration of the tromethamine-based suspension had the unexpected effect on fine ocular hloavattabiiiiy ot Compound-ί in :he poster lor segment The ocular bioavaiiahility of Compound-I in She posterior segment 'was observed to be directly proportional to the totaf amount of drug administered finsotubie ptus soluble, see Table 7). Although the insoluble drug particulates were not readily available to anterior segment tissues: the inherent and unique physicochemical properties c-f Compound-f allowed both insoluble and sofuble components to gain entry to posterior segment tissues, such as ihe choroid and retina. Consequently. even higner drug ooncentratforis than those achieved with Ge! Drop formuiaiions containing equivalent amounts of the active agent were achieved with the tromethamine-based suspension. Thus, tromethamine-based suspension provided: a) improved corneal tolerability and b} increased bioavailabllity Io the posterior segment, particularly to the choroid, the primary target tissue for {resting neovascular (wet) AMD. EXAMPLE 4

Cyctedexiofi-foased soteffon (not in accordance with the present invention) [0237] Cycfodexirins. which are cyclic oligosaccharides made up of six io eight dextrose units (α-, β-, and γ-CDs) joined through one to four bonds, are well-known tor their ability Io act as a solubilizing agent lot relaslvety Insoluble drugs. See Stella & He. Cyciodextrlns, Toxicol. Pathol,, 36; 30-42 (2008).

[0238] A clinical formulation of Compound-! or its free base ophthalmic Solution in 2-hydroxypropyl-|5-cyclodextrm (ΗΡ-β-CD, KLEPTOSE© HPS) al equal Io or more than 1 6 molar ratio or Sulfobulylether-p-cyclodextrln (SBE-'S-CD, CAPT!SOL®)ai β at equal to or more than i :2 ratio providee solubility with clinical dose strengths of 0.1-1.0% Compound-i. [0239] Cyctodexirin-based solutions of Compound-! or its free base not only improved solubility of the active agent into a uniform solution, but, upon topical ocutar administration, also had a novel and previously unobserved characteristic ot significantty increased therapeutic index of the active agent at -he posterior segment of the eye. The solution reduced anterior segment exposure, thereby providing increased concentration of the active in She solution and increased delivery frequency, which maintained high posterior segment concentrations. Both of these beneficiet characteristics are related to She known property of cyclodexirin to form hydrophilic complexes with hydrophobic drugs. See Sfoiia & He, Cycfo-dex.tnns, Toxicol. Pathol,, 36: 30-42 (2008). When formulated with Compound-l or its free base, cyclodextrin formed a clear, colcriess solution and exhibited water-like viscosity. Following topical ocular administration, the Compound-l/cy-clodextnn complex had the appearance oi being pharrnaoofogically inactive and metabolically inert The Compound-li'cyciodex-na complex conferred cornea! tolerability until cyclodexirin spontaneously dissociated from the active agent, thus making available high concentration of Con-pound I at its intended site of sciion in the posterior segment of the eye. e.g?., choroid and retina, [0240] During topical ocuiar dosing studies lasting from 1 Io 30 days in Dutch-belted rabbits, cyctodextrin-based solutions of Compound! demonstrated dramatically lowered corneal exposures compared to Gel Drop formulations (see Example 2) at similar drug cortcehtrabons. The use of cyciodexiriri-based.soluttohstof Compound-! provided an approximate 10x reddctidn !h cornea! concentrations, as compared to dosing with equimolar formulstions of the Get Drop. Consequently, after 30 days of topical ocular dosing of 0.6% Compound-! as a cyciodextnn-based solution, no untoward findings were attributed to test-article or vehicle. The cyctodextrin-based solution of Compound-i also achieved equal or significantly higher concentrations of drug within the posterior segment target tissues, such as at the centra! choroid and the centra! retina. The combined effects of decreasing comeai drug exposure so as Io avoid poor ocular toierabiiiiy, while increasing posterior segment bioavaifabiiity so as to Increase RTK inhibition, may significantly increase the therapeutic Index and corresponding benefit/ s) experienced by patients, [0241] For both suspension-based formulations (see Example 31 and the cyciodexinn formulations, the therapeutic window is expanded due to significantly reduced exposure OO-lOOX or 1-2 log reduction). The reduced exposure improves cornea! safety/toterability. which allows higher concentrations or frequency of dosing ot Compound-- to be administered topicaify. The: higher concentrations enables the drug to achieve higher back of the eye target, tissue concertfrations, which improves the therapeutic efficacy of Compound-i:.

[0.242] This study demonstrated that in rabbits and dogs, topical ocuiar dosing of ophthalmic gel drops, was associated with high cornea! tissue exposure (>1O0uM) and corresponding untoward observations in the anterior segment, such as discomfort, corneal and conjunctival inflammation, cornea! epithelial erosion and,tor thinning 3nd degeneration, in contrast, repeated topical ocular dosing of Compound-! ophthalmic solution produced comeai exposure that are roughly 5 to 10-fold lower than an equimolar dose of oph-hatmic ge! drops, and are free of untoward clinical or histopathologic tindings, Furthermore, topical ocular dosing with Compound-t ophthalmic solution achieved equat or higher target ther apeutic exposure in the central choroid in comparison to an equtmoiar dose of the ophthalmic gei drop. Overall ihe combination of decreased comes! exposure and corresponding improved ocuiar toierabiiity. while simultaneously maintaining or promoting drug delivery to the posterior segment target iissues. along with improved physicochemical stability, will provide greater benefit to patients compared to the ophthalmic Gei Drop formulation.,

EXAMPLES f- ro 5-day PK results with topicai ocular Coæpound-ί in Cyctdd&xtrin-based S'o/trifons (nut fit accordance with the present invention) [0243] Following topical ocuiar dose administration of various formulations and dosage regimens of Compound-l in Dutch Belied rabbits, ocuiar pharmacokinetics was investigated. Nine (9) different topical ocuiar formulations having three doses of Compound-l were administered either once per day (q.d - or twice perday ffc.i.d. i for 1, 4. or 5 consecutive days. The study design (see Tables 1OA-C) consisted of seventy-two (72) rabbits each receiving a 30 μ L bilateral topical ocular dose of one of three (3) Compound-i formulations, or vehicle formulation, using a positive displacement pipette, [0244] The composition of each Compound-! formulation is described m Tabte 8A. All rinses were administered within .:. 1 hour of the scheduled dose time. On day 1. Groups 1,2. 4-6, 8, 10, 11. 13,15, and 17 received one dose (q.d Ifor either one (1) or four {4) days. On days 1 through 4, Groups 3, 7,9, 12, 14. and -8reoeived b.i.d dosing approximately 8 hours apart at 7:00 AM and 3:00 PM for four t'4) days. Animats in Groups 18 and 19 received b.i.d dosing of vehicle only formulations for five- (5} consecutive days.

[0245] Ocular sampling occurred for Group 1 at 0 5. 1, 2,4. 8, or 24 hours post-dose relative to the day 1 dose . Ocular sampling occurred for Groups 2 and 6 at 1.8, and 24 hours post-dose relative fo the day 5 morning dose. Ocular sampling for Groups 3, 7. 8; 11, and 13 occurred a! 1 and 24 hours post-dose relative io fhe day 5 morning dose. Ocufar sampling for Groups 4. 9, 18, 12, 14, 15, 16, and 17 occurred ai 1 hour post-dose relative to the day 5 morning dose Group 5 ocular sampling occurred at 0.5, 1,2,4,8, and 24 hours post-dose relative to the day 1 dose. Animais in Groups 18 and 19 were followed only by clinical observations for five (5) days.

[0246] Aqueous humor, cornea, central and peripheral retina, and central and penpheral choroid samples were collected Aqueous humor, cornea, central retina, and central choroid samples were then assayed Peripheral retina and peripheral choroid samples were assayed only for Groups 1-8. 12.14, and 16 per study protocol.

[0247] Rabbit aqueous humor, cornea, central and peripheral retina: and central and peripheral choroid samples were analyzed Calibration curves were prepared in control matrix io determine the concentration of Compound-i in the various tissues, EXAMPLE 6 5-day PK results with topiaai Ocuiar GutapoUnd··! in Qycioddxtrin based Solutions (not In Upcntdaneb with the present invention) [0248] Following ocuiar dose administration of various dose regimens of topical ocular soiutions of Compound- i con taining nydroxypropyi-h-cycfodextrin ("HDi'-CD’h in Dutch-Belted rabbits, the ocular pharmacokinetics was calculated. Nme (9} different topical ocuiar soiutions having four different doses of Compound-! were administered either once per day (q.d ) or twice per day (b.i d ) for either 4 or 5 consecutive days. The study design consisted of forty (40- rabbits each receiving 3 30 pi bilateral topical ocular dose of one of four (4) Compound-! dosage strengths, using 3 positive displacement pipette [0249] All doses were administered with .ΐ 1 hour of ihe scheduled dose time, except on day 1 for Groups 1,4, and 10. Tiro first dose on day 1 was administered at 12:00 PM, and the second dose (for Groups 1 anti 10} was administered approximately 4 hours after. This was due fo delayed arrival of formulations, All other dosing for these groups was as scheduled. On day 1, Groups 4-8, and 11-12 received one dose (q.d.) for four (4} days. On days 1 through 4, Groups 1-3, and 9-10 received bid. dosing approximately 8 hours apart forfcur (4} days.

[0250] Ocuiar sampling occurred one hour following the first daily dose on day 5 for ai! groups, except Groups 5b and 8b, where ocular sampling occurred 24 hours after the first daily dose on day 4.

[0251] Blood samples for plasma collection were obtained just prior to scheduled euthanasia for at! animals. Aqueous humor, cornea, central and peripheral retina, and central and peripheral choroid samples were collected. Cornea, centra! retina, and central choroid samples from groups 1--12 were? assayed. Aqueous humor, peripheral retina, and peripheral choroid samples were not assayed. EXAMPLE 7

Gijfjcéiii/'ai/ons df CdippaUntf-f (in ytM) in Ifyriops Ocuiar Fluids and Tissues [0252] The bcuior solution oF Compound-l comprising cyciodextnn was prepared and tested in different groups of animats, upon topical rxcuiar administration of a solution of 0.4% (4 mg/ml) Compound-! and cyciodextrin, tire concentration of the active ager·· was measured in various (issues and fluids of ihe eye. Average concentration of Compound-! was measured m the central choroid, central retina, aqueous humor, ano cornea. Compound-! was in a solution {0.4% or 4 mg/mt.) with 8.41% KLEPTOSE-?® and 0 142% phosphate buffer; 8.3% KLEPTOSE© HPB .and 0 142%. phosphate: 4.88% CAPTtSOL® and 0.142% phosphate; or 4.88% CAPTISOL® and 0.122% phosphate. Sec- Table 10A-B.

[0253] The centra! choroid concentration of Compound-i was between 0.253 μΜ and 0.769 μΜ. See Tabie 10A. The central retina concentration cf Compound-i was between 0.0531 μΜ - 0.'24 μΜ. See Tabie 18A. The aqueous humor concentration of Compound-! was between 0,00313 μΜ - 0.0085-3 μΜ. See fable 10A. And the corneal concentration of Compound-! was 6.45 μΜ-38 μΜ. S'ee Tabie 10A. The cyciodextrinsused to prepare the solutions were KLEPTOSE© HPB or CAPTISOL®. See Tabie 10B. EXAMPLE 8

Octi/ar Toxicofogy Studies [0254] Dose-iimibng ocular toxieiiy was characterized by corneal and conjunctivaf findings In Dutch-Belied rabbits and beagle dogs. These ocuiar findings from repeat-dose toxicology studies with Compound-i ophthalmic gei drops were based upon rfimcal ophthalmic and hisiopathotogic evaluations and limited fo conjunctiva! hyperemia, chemos’s. congestion, and discharge, corneal opacification and epithelial erosion, and keratoconjunctivitis, No untoward siferaiions involving deeper structures of the eye (iris, tens, ciliary body, retina, choroid, sclera) or the optic nerve were observed. Retinal function was nonnat in al! test article, and vehicle treated groups during fuil-iieid eiectroretinograrns performed in rabbits.

[0255] Ttie objectives for the exploratory ocuiar toxicology studies were to identify a) a -opicai ocular formulation that was well tolerated and b) one that could achieve the targeted therapeutic concentrations of Cornpound-I in the central choroid.

[0256] Mean Compound-! ocular tissue .concentrations fallowing twice daily iopica! dosing with 0 3% Compound-i ophthatmic gel drop formulations with and without benzylaikonium chloride were highest in the cornea (23δ-260μΜ} »peripherat choroid <2.78-4.10 μ.Μ), centra! choroid (0,340-0.436μΜ;, peripheral retina (0.150-0.309μΜ) and aqueous humor (0.0197·0.0395μΜ· in Dutch-Belted rabbits [0257] Tris-based suspension iormuiations were weli tolerated, where-clinical ophthalmic-examinations revealed a notable absence of cornea! findings with onty a few sporadic incidences of mild conjunctivitis in Dutch-Belted rabbits. Moreover, the eyes from animals that had received 0.3% w/v Compound-! Tris-based suspension twice daly for 30 days were considered normal during microscopic evaluations. Mean Compound-! ocuiar tissue concentrations. assessed ai 1 tiour c. 15 minutes aiier the first daily topical ocular dose cm day 38 for the twice ciaiiy topicai dosing with 0.3% Compound-! Tris-based suspensions with and without benzylaikonium chloride, were highest in the cornea (2.83-3.50μΜ) »peftpherai choroid (0.781-1.21μΜ)< centra! choroid (0.303-0,31 ΘμΜ), peripheral retina (0.0819-0.0868μΜ), centra! retina (0 ()495-0.0592μ.Μ), and aqueous humor (0.80127--0.00145μΜ) [0258] Cyciodextrin-based solutions, using hydroxypropyi-beia-cyclodextrln (HP-ji-CD, KLEPTOSE® HPB), were well tolerated when administered tepicaily for 30 days, twice Catty ai 0.1% Compound-l (2,1 % KP-)3-CD), twice daily at 0.2% Compound-l ¢4.21% ΗΡ-β-CD), once or twice daily at 0.4% Compound-·! (8.41% HP-fi-CO). and once or twice daiiy at 0.6% Compound-! (up to 12.62% ΗΡ-β-CD) in Dutch-Belted rabbits. Moreover, m a simitar repeat dosing study, eycto-ciextnn-based solutions of 0.4% w/v Compound-! in KLEPTOSE© HPB, KLEPTOSE© HP. or CAPTSSOL© were weii-toierated when dosed twice daily for 24 days. No oven ocuiar toxicity related to Compound-! or vehicle treatment was found dunng clinical ophthaim-c or microscopic examinations in either study.

[0259] In the 24-day study, ocuiar tissue concentrations from t yes treatise1 with cyciodextrin-based solutions of Compound-1 were assessed at 1 hour * 15 minutes after the first daily topical ocular dose on cf ay 24 were in descending order hipest in the cornea (6.49-30p.M)» center-punch choroid (3 χ/2-0.769μΜ}> center-punchretina (0.0531-0.124) > aqueous humor (0 002-0.007} [0260] In summary, dose-irmiting cornea) toxicity was observed witb Compound-l ophthaimlc Gel Drop iormuiations. The ophthalmic Ge! Drop renders five-fold to fifteen -fold higher corneal concentrations of Compound-i compared to cyciodextrin based solution, and fifty-foict to hundred-fold higher corneal concentrations of Compound-! compared to Tris-based suspensions. Compound-i Tris-based suspensions and cyciodextrin-based solutions were well tolerated with no evidence of overt ocular toxicity. Dose levels that were wei! -oieratod for the eyciodex-rin-based solutions or Tris based suspensions of Compound-! when administered once or iwice daily ranged from about 0.005% to about 5.0% w/v for at ieast 30 days. Cyciodextnn-based solutions also provided the highest central choroid concentrations of Compound-! when using eguirnoier doses of the three formulations, and met or exceeded target fherapeutic concentrations.

EXAMPLES

Phase f Prot&coi for Dose-Pscaiatien Study in Patients with Neeva&ctifar AM& [0261] The Phase t study is a twelve-week, open -iabei.. dose-escalating, mutti-center iriat designed to evaiuate the safety, tolerability. and pharmacokinetics following topical ocular administration of Compound-i inpatients with nee-vascular age-refated macuiar degeneration (AMD). Up to 60 patients tots! are treated one to two times daily with topical ocular dosing of Compound-i ophthalmic solution tor three months, where three dcse-escalating monotherapy arms and one adjunct therapy arm using a single intravitreal injection of LUCENTIS© plus the maximatty-toierated monotherapy dose are planned ( :5 patients per treatment arm). Patients that meet pre-specified vision and CNV lesion criteria con-fi-med by an independent reading center are allowed to simultaneously discontinue topical ocuiar dosing and receive treatment with stanrfard-of-care.

[0262] Compound-l ophthalmic solution for ciinica! studies is manufactured in at toast 3 dosage strengths, ranging from 0.1 % to 1.6% (as Compound-!;. The strengths for the GLP batches are 0% (placebo), 0.1 %, 0.3%, 0.6%, and f .0% Compound-t HCS. Up to 2- to 3-foid incremental doses (approximately % log unit steps) are administered to succeeding cohorts. EXAMPLE 10 [0263] A "non-gel,” ”n on-viscous,” homogeneous ophthalmic solution topical -orrnutatiori thai is both physically and chemically stable over the drug strengths of 0.1-1 0% (1 So 1Q mg/ml) was prepared by measuring the Compound-l concentration, cyciodexinn complexing agent con cent rat ion, pH, arid ionicity, on Compound-! solubility and stability. A suitable buffering system prevents pH drift on stability at concentrations less than 1 rng/mL. Both phosphate and Tromel-amol (Trisi were evaluated as buffering agents. Sodium ohioride was used ίο adjust tonicity.

[0264] The product quality attributes are shown in i able 14.

Tabie 14: Product Quality Attributes

Formulation Preparation [0265] The formulations outlined Iii Tables 12 arid 13 were prepared using the general procedure listed.

[0266] The formutation was made up to volume with water for injection and stirred for 30 minutes at 500 rpm. Final pH was checked and adjusted with either. NaOH or HCI to the target range. Approximately Suit aliquots to directly filtered into semi-transparent omi LDPE bottles white continuously stirring st constant speed with the aid of Watson Marlow Pumpsii D tubing, fitted to a Ffextcon filler and attached to 0.2 micron PVDF capsule fifier. Samples are stored at 2-8 ’C until al! sample preparation is complete. Ail samples will then he submitted to analytical for storage and testing.

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by ihe applicant is for fhe reader's CfloyeriiifoC® Only. itdaps hat farm part of fhé European patent document Even though gteat care has been taken in compiling ihe references. errors or omissions cannot be excluded end the EPO diScfe/ms SC' iiab'ldy ”> fo/S repaid

Patent documents cited in the description * US 2005074497 A [COOT] » US 0215704 0 [0081]

Non-patent literature cited in the description * STELLA: HE. Cyc/odexfnns. Toxicoi. Pathol.. 2008, vol, 38, 30-42 [0163] [0165] [0237] (0239]

Claims

A topical eye formulation comprising: a. An active agent of formula II:

or a pharmaceutically acceptable salt thereof and b. pharmaceutically acceptable excipients; wherein the active agent or pharmaceutically acceptable salt is present in 0.1% to 2.0% w / v so that the formulation forms a suspension.

The formulation of claim 1 comprising 0.2% to 1% of tromethamine.

The formulation of claim 2 comprising a non-ionic liquid polymer of the alkylaryl polyether alcohol type.

The formulation of claim 3, wherein the non-ionic liquid polymer of the alkylaryl polyether alcohol type is tyloxapol.

The formulation of claim 2 comprising a hydrophilic nonionic surfactant.

The formulation of claim 5, wherein the hydrophilic nonionic surfactant is poloxamer.

The formulation of claim 1 comprising 1% to 2% glycerine.

The formulation of claim 1 comprising 0.6% tromethamine and 1% to 2% glycerine.

The formulation of claim 1, further comprising a thickener.

The formulation of claim 9, wherein the thickener is hydroxyethyl cellulose (HEC) or hydroxypropyl methyl cellulose (HPMC).

The formulation of claim 9, wherein the thickener is HPMC or a salt thereof.

The formulation of claim 9, wherein the thickener is carboxymethyl cellulose or a salt thereof.

The formulation of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride salt of the formula:

The formulation of claim 1 comprising 0.1% to 1.0% w / v of the active agent or a pharmaceutically acceptable salt thereof.

The formulation of claim 1 comprising 1.0% to 2.0% w / v of the active agent or a pharmaceutically acceptable salt thereof.

The formulation of claim 1, comprising one or more of a buffering agent, a tonicity agent, a preservative, a solvent, a pH modifier, a thickening agent and a chelating agent.

The formulation of claim 16, wherein the buffering agent is a citrate buffer.

The formulation of claim 1 comprising 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0 , 9%, 1.0%, or 2.0% w / v of the active agent or a pharmaceutically acceptable salt thereof and 0.6% w / v of tromethamine.

The formulation of claim 1 having a pH of 4.5 to 7.5 at or below 40 ° C, or a pH of 5.0 to 7.0 at or below 40 ° C, preferably a pH value of 6.0 at or below 40 ° C.

The formulation of claim 1 for use in accessing the posterior segment of the eye and / or for use in the treatment and / or amelioration of a disease of the posterior segment of the eye, selected from the group consisting of: diabetic retinopathy, age-related macular degeneration (AMD), pathological choroidal neovascularization (CNV), pathological retinal neovascularization, uveitis, retinal vein occlusion, ocular trauma, surgically induced edema, surgically induced neovascularization, cystoid macular edema, ocular ischemia, prematurity retinopathy, Coat disease, sickle cell osteopathy, and sickle cell retinopathy. proliferative diabetic retinopathy or diabetic macular edema, or preferably where AMD is neovascular AMD, dry AMD or geographical atrophy, more preferably where the neovascular AMD is wet or exudative AMD, or preferably where CNV is related to high myopia, trauma, sickle cell disease, ocular histopla. mucus, angioid streaks, traumatic choroidal rupture, optic nerve or some retinal dystrophies, preferably where the pathological retinal neovascularization is related to sickle cell orthopathy, Eales disease, ocular ischemic syndrome, carotico-cavernous fistula, familial exudative vitreous disc

birdshot retinochoroidopathy, retinal vasculitis, sarcoidosis or toxoplasmosis, preferably where the retinal vein occlusion is a central or branched occlusion.

The formulation for use according to claim 20, comprising administering the formulation 1, 2, 3, or 4 times daily consecutive days or alternating days, wherein the formulation is preferably administered once or twice daily consecutive days or alternating days.

The formulation for use according to claim 20, comprising administering twice daily consecutive days or alternating days of the formulation containing 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, or 2.0% w / v of the active agent or a pharmaceutically acceptable salt thereof.

The formulation for use according to claim 22, wherein the formulation is administered to the eye or both eyes.